Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect

ABSTRACT

Pharmaceutical compositions are provided comprising one or more orally deliverable dose units, each comprising a selective cyclooxygenase-2 inhibitory drug of low water solubility in a therapeutically effective amount, wherein the drug is present in the form of solid particles, about 25% to 100% by weight of which are smaller than 1 μm. The compositions are useful in treatment or prophylaxis of cyclooxygenase-2 mediated conditions and disorders and have particular advantages where rapid onset of therapeutic effect is desired.

CROSS REFERENCE TO RELATED APPLICATION

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/731,350 and claims priority of U.S. provisionalapplication Serial No. 60/169,856 filed on Dec. 9, 1999.

FIELD OF THE INVENTION

[0002] The present invention relates to orally deliverablepharmaceutical compositions containing a selective cyclooxygenase-2inhibitory drug as an active ingredient, to processes for preparing suchcompositions, to methods of treatment of cyclooxygenase-2 mediateddisorders comprising orally administering such compositions to asubject, and to use of such compositions in manufacture of medicaments.

BACKGROUND OF THE INVENTION

[0003] Numerous compounds have been reported having therapeuticallyand/or prophylactically useful selective cyclooxygenase-2 (COX-2)inhibitory effect, and have been disclosed as having utility intreatment or prevention of specific COX-2 mediated disorders or of suchdisorders in general. Among such compounds are a large number ofsubstituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No.5,760,068 to Talley et al., including for example the compound4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,also referred to herein as celecoxib (I), and the compound4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide,also referred to herein as deracoxib (II).

[0004] Other compounds reported to have therapeutically and/orprophylactically useful selective COX-2 inhibitory effect aresubstituted isoxazolyl benzenesulfonamides as reported in U.S. Pat. No.5,633,272 to Talley et al., including the compound4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also referred toherein as valdecoxib (III).

[0005] Still other compounds reported to have therapeutically and/orprophylactically useful selective COX-2 inhibitory effect aresubstituted (methylsulfonyl)phenyl furanones as reported in U.S. Pat.No. 5,474,995 to Ducharme et al., including the compound3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also referred toherein as rofecoxib (IV).

[0006] U.S. Pat. No. 5,981,576 to Belley et al. discloses a furtherseries of (methylsulfonyl)phenyl furanones said to be useful asselective COX-2 inhibitory drugs, including3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-oneand3-(1-cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.

[0007] U.S. Pat. No. 5,861,419 to Dube et al. discloses substitutedpyridines said to be useful as selective COX-2 inhibitory drugs,including for example the compound5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine(V).

[0008] European Patent Application No. 0 863 134 discloses the compound2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-onesaid to be useful as a selective COX-2 inhibitory drug.

[0009] U.S. Pat. No. 6,034,256 discloses a series of benzopyrans said tobe useful as selective COX-2 inhibitory drugs, including the compound(S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid(VI).

[0010] Many selective COX-2 inhibitory drugs, including celecoxib,deracoxib, valdecoxib and rofecoxib, are hydrophobic and have lowsolubility in water. This has presented practical difficulties informulating such drugs for oral administration, particularly where earlyonset of therapeutic effect is desired or required.

[0011] Illustratively, the formulation of celecoxib for effective oraladministration to a subject has hitherto been complicated by the uniquephysical and chemical properties of celecoxib, particularly its lowsolubility and factors associated with its crystal structure, includingcohesiveness, low bulk density and low compressibility. Celecoxib isunusually insoluble in aqueous media. Unformulated celecoxib is notreadily dissolved and dispersed for rapid absorption in thegastrointestinal tract when administered orally, for example in capsuleform. In addition, unformulated celecoxib, which has a crystalmorphology that tends to form long cohesive needles, typically fusesinto a monolithic mass upon compression in a tableting die. Even whenblended with other substances, the celecoxib crystals tend to separatefrom the other substances and agglomerate together during mixing of thecomposition resulting in a non-uniformly blended composition containingundesirably large aggregates of celecoxib. Therefore, it is difficult toprepare a pharmaceutical composition containing celecoxib that has thedesired blend uniformity. Further, handling problems arising for examplefrom the low bulk density of celecoxib are encountered duringpreparation of celecoxib compositions. Accordingly, a need exists forsolutions to numerous problems associated with preparation ofcompositions and dosage forms comprising celecoxib, particularly orallydeliverable dose units.

[0012] Further, there exists an especial need for orally deliverableformulations of selective COX-2 inhibitory drugs of low water solubilityincluding celecoxib, such formulations providing more rapid onset oftherapeutic effect than the corresponding unformulated drugs or knownformulations of these drugs. To the extent that rapid onset oftherapeutic effect is related to rapid early absorption of the drug inthe gastrointestinal tract, there is an especial need for orallydeliverable formulations having pharmacokinetic properties indicative ofsuch rapid early absorption, such as a greater maximum blood serumconcentration of the drug (i.e., C_(max)), a shorter time to reach athreshold blood serum concentration of the drug for therapeutic effect,and/or a shorter time to reach the C_(max) (i.e., T_(max)) than thecorresponding unformulated drugs or known formulations of these drugs.

[0013] It would be even more especially useful if formulations could bedeveloped having not only advantages of early absorption and thereforerapid onset of therapeutic effect, but also superior overallbioavailability, such as can be measured pharmacokinetically as the areaunder the curve of blood serum concentration (i.e., AUC).

[0014] As indicated hereinbelow, treatment with selective COX-2inhibitory drugs including celecoxib is indicated or potentiallyindicated in a very wide array of COX-2 mediated conditions anddisorders. It would be of benefit to provide formulations exhibitingpharmacokinetics consistent with rapid onset of therapeutic effectespecially for treatment of acute disorders where early relief from painor other symptoms is desired or required.

[0015] Such formulations would represent a significant advance in thetreatment of COX-2 mediated conditions and disorders.

[0016] Selective COX-2 inhibitory drugs including celecoxib that are oflow solubility in water are most conveniently formulated in solidparticulate form. The individual or primary particles of the drug candispersed in a liquid medium, as in a suspension formulation, or can beaggregated to form secondary particles or granules that can beencapsulated to provide a capsule dosage form, or compressed or moldedto provide a tablet dosage form.

[0017] Numerous processes are known for preparing drug formulationshaving primary particle sizes in a desired range, or having a desiredmean particle size, or having a particle size distribution characterizedby a parameter such as D₉₀, which is defined herein as a linear measureof diameter having a value such that 90% by weight of particles in theformulation, in the longest dimension of the particles, are smaller thanthat diameter. Other particle size parameters used herein are defined insimilar fashion; for example D₁₀, D₂₅ and D₅₀ parameters relate tolinear measures of diameter having values such that 10%, 25% and 50%respectively by weight are smaller than that diameter.

[0018] For consistency with prior publications, the terms“microparticle” and “nanoparticle” are defined herein as in U.S. Pat.No. 5,384,124 to Courteille et al., to refer to particles havingrespectively a diameter of about 1 μm to about 2000 μm, and a diameterof less than about 1 μm (1000 nm). The preparation of microparticles andnanoparticles, according to U.S. Pat. No. 5,384,124, “is principallyused to retard dissolution of active principles”. However, U.S. Pat. No.5,145,684 to Liversidge et al. discloses nanoparticulate compositionssaid to provide “unexpectedly high bioavailability” of drugs,particularly drugs having low solubility in a liquid medium such aswater. International Publication No. WO 93/25190 providespharmacokinetic data from a rat study indicating a higher apparent rateof absorption from oral administration of a nanoparticulate (averageparticle size 240-300 nm) than from oral administration of amicroparticulate (particle size range 20-30 μm) dispersion of naproxen.

[0019] Numerous processes for preparation of nanoparticulatecompositions of therapeutic agents are known. Typically these processesuse mechanical means, such as milling, to reduce particle size to a nano(less than 1 μm) range, or precipitate nano-sized particles fromsolution.

SUMMARY OF THE INVENTION

[0020] According to the present invention, a poorly water solubleselective COX-2 inhibitory drug such as celecoxib provides more rapidonset of therapeutic effect if, upon oral administration of acomposition comprising the drug, the drug exhibits pharmacokineticproperties leading to a greater maximum blood serum concentration(C_(max)) and/or a shorter time following the administration to reachthat maximum (T_(max)) or to reach a threshold concentration fortherapeutic effect.

[0021] In the case of celecoxib, the threshold blood serum concentrationconsistent with therapeutic effect depends on the individual subject,the nature of the disorder being treated and other factors, but forpresent purposes is about 50 ng/ml. For selective COX-2 inhibitory drugsgenerally, the threshold concentration is that providing therapeuticeffect equivalent to celecoxib at a blood serum concentration of about50 ng/ml.

[0022] It is contemplated that a greater C_(max), a shorter T_(max)and/or a shorter time to threshold concentration are obtained byreduction of size of solid particles comprising the drug such that asubstantial portion by weight of the particles are smaller than about 1μm in diameter, in the longest dimension of the particles. Without beingbound by theory, it is believed that the greater C_(max), the shorterT_(max) and/or the shorter time to threshold concentration result fromfaster dissolution of the drug when particle size is reduced to lessthan about 1 μm.

[0023] Accordingly, there is now provided a pharmaceutical compositioncomprising one or more orally deliverable dose units, each comprising aselective COX-2 inhibitory drug of low water solubility in atherapeutically effective amount, wherein the drug is present in solidparticles having a D₉₀ particle size of about 0.01 to about 200 μm, asufficient portion by weight of the particles being smaller than 1 μm toprovide a substantially higher C_(max) and/or a substantially shorterT_(max) and/or a substantially shorter time to threshold concentrationby comparison with an otherwise similar composition whereinsubstantially all of the particles are larger than 1 μm. Preferredcompositions of the invention additionally exhibit enhanced totalbioavailability (as measured by AUC) by comparison with otherwisesimilar compositions wherein substantially all of the particles arelarger than 1 μm.

[0024] There is also provided a pharmaceutical composition comprisingone or more orally deliverable dose units, each comprising a selectiveCOX-2 inhibitory drug of low water solubility in a therapeuticallyeffective amount, wherein the drug is present in solid particles havinga D₉₀ particle size of about 0.01 to about 200 μm, and wherein about 25%to 100% by weight of the particles are smaller than 1 μm.

[0025] The dose units comprising the composition can be in the form ofdiscrete solid articles such as tablets, pills, hard or soft capsules,lozenges, sachets or pastilles; alternatively the composition can be inthe form of a substantially homogeneous flowable mass, such as aparticulate or granular solid or a liquid suspension, from which singledose units are measurably removable.

[0026] Also provided is a method of treating a medical condition ordisorder in a subject where treatment with a COX-2 inhibitor isindicated, comprising orally administering one or more dose units of acomposition of the invention one to about six times a day, preferablyonce or twice a day. Such a method is particularly useful where themedical condition or disorder is accompanied by acute pain.

[0027] Other features of this invention will be in part apparent and inpart pointed out hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0028]FIG. 1 presents particle size data for celecoxib dispersions D1-D4prepared as described in Example 1, as measured by Fraunhoferdiffraction.

[0029]FIG. 2 shows optical micrographs of samples taken from dispersionsD1-D4 under non-polarized (left) and polarized (right) light.

[0030]FIG. 3 shows time-course of in vitro dissolution of dispersionsD1-D4.

[0031]FIG. 4 is a schematic representation of apparatus used to performthe in vitro dissolution assay of Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Selective COX-2 inhibitory drugs for which the present inventionis useful are drugs that inhibit COX-2 to a therapeutically usefuldegree while causing markedly less inhibition of cyclooxygenase-1(COX-1) than conventional nonsteroidal anti-inflammatory drugs (NSAIDs).

[0033] The invention applies particularly to selective COX-2 inhibitorydrugs of low water solubility, especially those having a solubility indistilled water at 25° C. lower than about 10 g/l, preferably lower thanabout 1 g/l.

[0034] The term “oral administration” herein includes any form ofdelivery of a therapeutic agent or a composition thereof to a subjectwherein the agent or composition is placed in the mouth of the subject,whether or not the agent or composition is swallowed. Thus “oraladministration” includes buccal and sublingual as well as esophagealadministration. Absorption of the agent can occur in any part or partsof the gastrointestinal tract including the mouth, esophagus, stomach,duodenum, ileum and colon.

[0035] The term “orally deliverable” herein means suitable for oraladministration.

[0036] The term “dose unit” herein means a portion of a pharmaceuticalcomposition that contains an amount of a therapeutic agent, in thepresent case a selective COX-2 inhibitory drug, suitable for a singleoral administration to provide a therapeutic effect. Typically one doseunit, or a small plurality (up to about 4) of dose units, administeredas a single oral administration, provides a sufficient amount of theagent to result in the desired effect.

[0037] The term “present in solid particles” as applied to a selectiveCOX-2 inhibitory drug herein encompasses compositions wherein the solidparticles consist essentially of the drug and compositions where thesolid particles comprise the drug in intimate mixture with one or moreother ingredients. These other ingredients can include one or moretherapeutic agents other than the selective COX-2 inhibitory drug and/orone or more pharmaceutically acceptable excipients.

[0038] The term “excipient” herein means any substance, not itself atherapeutic agent, used as a carrier or vehicle for delivery of atherapeutic agent to a subject or added to a pharmaceutical compositionto improve its handling, storage, disintegration, dispersion,dissolution, release or organoleptic properties or to permit orfacilitate formation of a dose unit of the composition into a discretearticle such as a capsule or tablet suitable for oral administration.Excipients can include, by way of illustration and not limitation,diluents, disintegrants, binding agents, adhesives, wetting agents,lubricants, glidants, substances added to mask or counteract adisagreeable taste or odor, flavors, dyes, fragrances, and substancesadded to improve appearance of the composition.

[0039] The term “substantially homogeneous” with reference to apharmaceutical composition that comprises several components means thatthe components are sufficiently mixed such that individual componentsare not present as discrete layers and do not form concentrationgradients within the composition.

[0040] Compositions of the invention comprise one or more orallydeliverable dose units. Each dose unit comprises a selective COX-2inhibitory drug, illustratively celecoxib, in a therapeuticallyeffective amount that is preferably about 5 mg to about 1000 mg, morepreferably about 10 mg to about 1000 mg.

[0041] It will be understood that a therapeutically effective amount ofa selective COX-2 inhibitory drug for a subject is dependent inter aliaon the body weight of the subject. Where the drug is celecoxib and thesubject is a child or a small animal (e.g., a dog), for example, anamount of celecoxib relatively low in the preferred range of about 10 mgto about 1000 mg is likely to provide blood serum concentrationsconsistent with therapeutic effectiveness. Where the subject is an adulthuman or a large animal (e.g., a horse), achievement of such blood serumconcentrations of celecoxib are likely to require dose units containinga relatively greater amount of celecoxib. For an adult human, atherapeutically effective amount of celecoxib per dose unit in acomposition of the present invention is typically about 50 mg to about400 mg. Especially preferred amounts of celecoxib per dose unit areabout 100 mg to about 200 mg, for example about 100 mg or about 200 mg.

[0042] For other selective COX-2 inhibitory drugs, an amount of the drugper dose unit can be in a range known to be therapeutically effectivefor such drugs. Preferably, the amount per dose unit is in a rangeproviding therapeutic equivalence to celecoxib in the dose rangesindicated immediately above.

[0043] Dose units of celecoxib compositions of the invention typicallycontain about 10 mg to about 400 mg of celecoxib, for example, a 10, 20,37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 mg dose ofcelecoxib. Preferred dose units contain about 25 mg to about 400 mg ofcelecoxib. More preferred dose units contain about 50 mg to about 200 mgof celecoxib. A particular dose unit can be selected to accommodate thedesired frequency of administration used to achieve a specified dailydosage. The amount of the unit dosage form of the composition that isadministered and the dosage regimen for treating the condition ordisorder will depend on a variety of factors, including the age, weight,sex and medical condition of the subject, the severity of the conditionor disorder, the route and frequency of administration, and theparticular selective COX-2 inhibitory drug selected, and thus may varywidely. One or more dose units can be administered up to about 6 times aday. It is contemplated, however, that for most purposes a once-a-day ortwice-a-day administration regimen provides the desired therapeuticefficacy.

[0044] A composition of the invention preferably contains about 1% toabout 95%, preferably about 10% to about 90%, more preferably about 25%to about 85%, and still more preferably about 30% to about 80%, byweight of the selective COX-2 inhibitory drug, alone or in intimatemixture with one or more excipients. The drug is at least partly innanoparticulate form, i.e., in the form of solid particles of diameterless than 1 μm in the longest dimension of the particles.

[0045] The effects on pharmacokinetic properties of reducing particlesize from the microparticle range (greater than 1 μm diameter) to thenanoparticle range are generally unpredictable for any particular drugor class of drugs. According to the present invention, for selectiveCOX-2 inhibitory drugs of low water solubility, nanoparticulatecompositions exhibit higher C_(max), shorter T_(max) and/or shorter timeto threshold concentration than microparticulate compositions. In oneembodiment of the invention, therefore, the percentage by weight of theparticles that are nanoparticles is sufficient to provide asubstantially higher C_(max), a substantially shorter T_(max) and/or asubstantially shorter time to threshold concentration by comparison witha comparative composition wherein substantially all of the particles arelarger than 1 μm. Preferably a composition of this embodiment has asufficient percentage by weight of nanoparticles to provide asubstantially shorter time to threshold concentration, more preferably asufficient percentage by weight of nanoparticles to provide both asubstantially shorter time to threshold concentration and asubstantially shorter T_(max), and more preferably still a sufficientpercentage by weight of nanoparticles to provide both these advantagestogether with a substantially higher C_(max), than the comparativecomposition.

[0046] When administered orally to a fasting adult human subject, acelecoxib 100 mg dose unit of the invention typically provides a bloodserum concentration of celecoxib of at least about 50 ng/ml within 30minutes of oral administration; preferred compositions achieve such aconcentration in as little as 15 minutes. This early rise in blood serumconcentration is believed to be associated with the rapid onset oftherapeutic effect achieved by compositions of the present invention.

[0047] Also when administered orally to a fasting adult human subject, acelecoxib 100 mg dose unit preferably exhibits a T_(max) of less thanabout 90 minutes, more preferably less than about 60 minutes and mostpreferably less than about 45 minutes, and a C_(max) of at least about100 ng/ml, more preferably at least about 200 ng/ml.

[0048] For selective COX-2 inhibitory drugs other than celecoxib,suitable doses and blood serum concentration parameters can beidentified based on published information, including that contained inpatent literature cited herein, enabling estimation of relativetherapeutic potency of such drugs by comparison with celecoxib.

[0049] In another embodiment of the invention, the selective COX-2inhibitory drug, illustratively celecoxib, is present in solid particleshaving a D₉₀ particle size of about 0.01 to about 200 μm, wherein about25% to 100% by weight of the particles are nanoparticles. Where thepercentage by weight of nanoparticles is relatively low, for exampleabout 25% to about 50%, preferably the D₉₀ particle size is about 0.01to about 100 μm, more preferably about 0.01 to about 75 μm, still morepreferably about 0.01 to about 40 μm, and even more preferably about0.01 to about 25 μm. Particle size can vary continuously across thenanoparticulate and microparticulate range, or the composition can havea bimodal or multimodal particle size distribution, with one set ofparticles having a D₉₀ particle size less than 1 μm and another set ofparticles having a D₉₀ particle size substantially greater than 1 μm. Itis generally preferred that at least about 50% by weight, and especiallypreferred that at least about 75% by weight, of the particles arenanoparticles. In one embodiment substantially all of the particles aresmaller than 1 μm, i.e., the percentage by weight of nanoparticles is100% or close to 100%.

[0050] Primary particles, generated for example by milling or grinding,or by precipitation from solution, can agglomerate to form secondaryaggregate particles. The term “particle size” as used herein refers tosize, in the longest dimension, of primary particles, unless the contextdemands otherwise.

[0051] In a preferred embodiment, a composition of the invention has aweight average particle size of about 100 nm to about 1000 nm, morepreferably about 100 nm to about 900 nm, for example about 200 nm toabout 400 nm, or about 500 nm to about 900 nm. The drug can be incrystalline or amorphous form in the nanoparticles. Processes forpreparing nanoparticles that involve milling or grinding typicallyprovide the drug in crystalline form, whereas processes that involveprecipitation from solution frequently but not invariably provide thedrug partly or wholly in amorphous form.

[0052] Compositions of the invention comprise a selective COX-2inhibitory drug of low water solubility, for example celecoxib, partlyor wholly in nanoparticulate form as described above, optionallytogether with one or more excipients selected from diluents,disintegrants, binding agents, wetting agents and lubricants. In oneembodiment, nanoparticles comprising the drug have a surface modifyingagent adsorbed on the surface thereof. In another embodiment,nanoparticles of the drug are contained in a matrix formed by a polymer.Preferably at least one of the excipients is a water soluble diluent orwetting agent. Such a water soluble diluent or wetting agent assists inthe dispersion and dissolution of the drug when a composition of theinvention is ingested. Preferably both a water soluble diluent and awetting agent are present.

[0053] A composition of the invention can be a substantially homogeneousflowable mass such as a particulate or granular solid or a liquid, or itcan be in the form of discrete articles such as capsules or tablets eachcomprising a single dose unit.

[0054] In a composition that is a substantially homogeneous flowablemass, single dose units are measurably removable using a suitablevolumetric measuring device such as a spoon or cup. Suitable flowablemasses include, but are not limited to, powders and granules.Alternatively, the flowable mass can be a suspension having the drug ina solid particulate phase dispersed in a liquid phase, preferably anaqueous phase. At least a portion of the particulate phase isnanoparticulate. In preparing such a suspension, use of a wetting agentsuch as polysorbate 80 or the like is likely to be beneficial. Asuspension can be prepared by dispersing nanoparticulate or partiallynanoparticulate drug in the liquid phase; alternatively the drug can beprecipitated from solution in a solvent such as an alcohol, preferablyethanol. The aqueous phase preferably comprises a palatable vehicle suchas water, syrup or fruit juice, for example apple juice.

[0055] The selective COX-2 inhibitory drug can be any such drug known inthe art, including without limitation compounds disclosed in the patentsand publications listed below, each of which is individuallyincorporated herein by reference.

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[0142] U.S. Pat. No. 6,083,969 to Ferro et al.

[0143] U.S. Pat. No. 6,096,753 to Spohr et al.

[0144] U.S. Pat. No. 6,133,292 to Wang et al.

[0145] International Patent Publication No. WO 94/15932.

[0146] International Patent Publication No. WO 96/19469.

[0147] International Patent Publication No. WO 96/26921.

[0148] International Patent Publication No. WO 96/31509.

[0149] International Patent Publication No. WO 96/36623.

[0150] International Patent Publication No. WO 96/38418.

[0151] International Patent Publication No. WO 97/03953.

[0152] International Patent Publication No. WO 97/10840.

[0153] International Patent Publication No. WO 97/13755.

[0154] International Patent Publication No. WO 97/13767.

[0155] International Patent Publication No. WO 97/25048.

[0156] International Patent Publication No. WO 97/30030.

[0157] International Patent Publication No. WO 97/34882.

[0158] International Patent Publication No. WO 97/46524.

[0159] International Patent Publication No. WO 98/04527.

[0160] International Patent Publication No. WO 98/06708.

[0161] International Patent Publication No. WO 98/07425.

[0162] International Patent Publication No. WO 98/17292.

[0163] International Patent Publication No. WO 98/21195.

[0164] International Patent Publication No. WO 98/22457.

[0165] International Patent Publication No. WO 98/32732.

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[0167] International Patent Publication No. WO 98/43966.

[0168] International Patent Publication No. WO 98/45294.

[0169] International Patent Publication No. WO 98/47871.

[0170] International Patent Publication No. WO 99/01130.

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[0172] International Patent Publication No. WO 99/01452.

[0173] International Patent Publication No. WO 99/01455.

[0174] International Patent Publication No. WO 99/10331.

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[0196] International Patent Publication No. WO 00/24719.

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[0201] European Patent Application No. 0 799 823.

[0202] European Patent Application No. 0 846 689.

[0203] European Patent Application No. 0 863 134.

[0204] European Patent Application No. 0 985 666.

[0205] Compositions of the invention are especially useful for compoundshaving the formula (VI):

[0206] where R³ is a methyl or amino group, R⁴ is hydrogen or a C₁₋₄alkyl or alkoxy group, X is N or CR⁵ where R⁵ is hydrogen or halogen,and Y and Z are independently carbon or nitrogen atoms defining adjacentatoms of a five- to six-membered ring that is unsubstituted orsubstituted at one or more positions with oxo, halo, methyl orhalomethyl groups. Preferred such five- to six-membered rings arecyclopentenone, furanone, methylpyrazole, isoxazole and pyridine ringssubstituted at no more than one position.

[0207] Illustratively, compositions of the invention are suitable forcelecoxib, deracoxib, valdecoxib, rofecoxib,5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine,2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-oneand (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid, more particularly celecoxib and valdecoxib, and most particularlycelecoxib.

[0208] The invention is illustrated herein with particular reference tocelecoxib, and it will be understood that any other selective COX-2inhibitory compound of low solubility in water can, if desired, besubstituted in whole or in part for celecoxib in compositions hereindescribed.

[0209] Compositions of the invention are useful in treatment andprevention of a very wide range of disorders mediated by COX-2,including but not restricted to disorders characterized by inflammation,pain and/or fever. Such compositions are especially useful asanti-inflammatory agents, such as in treatment of arthritis, with theadditional benefit of having significantly less harmful side effectsthan compositions of conventional nonsteroidal anti-inflammatory drugs(NSAIDs) that lack selectivity for COX-2 over COX-1. In particular, suchcompositions have reduced potential for gastrointestinal toxicity andgastrointestinal irritation including upper gastrointestinal ulcerationand bleeding, reduced potential for renal side effects such as reductionin renal function leading to fluid retention and exacerbation ofhypertension, reduced effect on bleeding times including inhibition ofplatelet function, and possibly a lessened ability to induce asthmaattacks in aspirin-sensitive asthmatic subjects, by comparison withcompositions of conventional NSAIDs. Thus compositions of the inventioncomprising a selective COX-2 inhibitory drug are particularly useful asan alternative to conventional NSAIDs where such NSAIDs arecontraindicated, for example in patients with peptic ulcers, gastritis,regional enteritis, ulcerative colitis, diverticulitis or with arecurrent history of gastrointestinal lesions; gastrointestinalbleeding, coagulation disorders including anemia such ashypoprothrombinemia, hemophilia or other bleeding problems; kidneydisease; or in patients prior to surgery or patients takinganticoagulants.

[0210] Such compositions are useful to treat a variety of arthriticdisorders, including but not limited to rheumatoid arthritis,spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupuserythematosus and juvenile arthritis.

[0211] Such compositions are also useful in treatment of asthma,bronchitis, menstrual cramps, preterm labor, tendinitis, bursitis,allergic neuritis, cytomegalovirus infectivity, apoptosis includingHIV-induced apoptosis, lumbago, liver disease including hepatitis,skin-related conditions such as psoriasis, eczema, acne, burns,dermatitis and ultraviolet radiation damage including sunburn, andpost-operative inflammation including that following ophthalmic surgerysuch as cataract surgery or refractive surgery.

[0212] Such compositions are useful to treat gastrointestinal conditionssuch as inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome and ulcerative colitis.

[0213] Such compositions are useful in treating inflammation in suchdiseases as migraine headaches, periarteritis nodosa, thyroiditis,aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type Idiabetes, neuromuscular junction disease including myasthenia gravis,white matter disease including multiple sclerosis, sarcoidosis,nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis,nephritis, hypersensitivity, swelling occurring after injury includingbrain edema, myocardial ischemia, and the like.

[0214] Such compositions are useful in treatment of ophthalmic diseases,such as retinitis, conjunctivitis, retinopathies, uveitis, ocularphotophobia, and of acute injury to the eye tissue.

[0215] Such compositions are useful in treatment of pulmonaryinflammation, such as that associated with viral infections and cysticfibrosis, and in bone resorption such as that associated withosteoporosis.

[0216] Such compositions are useful for treatment of certain centralnervous system disorders, such as cortical dementias includingAlzheimer's disease, neurodegeneration, and central nervous systemdamage resulting from stroke, ischemia and trauma. The term “treatment”in the present context includes partial or total inhibition ofdementias, including Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholic dementia andsenile dementia.

[0217] Such compositions are useful in treatment of allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome and liverdisease.

[0218] Such compositions are useful in treatment of pain, including butnot limited to postoperative pain, dental pain, muscular pain, and painresulting from cancer. For example, such compositions are useful forrelief of pain, fever and inflammation in a variety of conditionsincluding rheumatic fever, influenza and other viral infectionsincluding common cold, low back and neck pain, dysmenorrhea, headache,toothache, sprains and strains, myositis, neuralgia, synovitis,arthritis, including rheumatoid arthritis, degenerative joint diseases(osteoarthritis), gout and ankylosing spondylitis, bursitis, bums, andtrauma following surgical and dental procedures.

[0219] Such compositions are useful for treating and preventinginflammation-related cardiovascular disorders, including vasculardiseases, coronary artery disease, aneurysm, vascular rejection,arteriosclerosis, atherosclerosis including cardiac transplantatherosclerosis, myocardial infarction, embolism, stroke, thrombosisincluding venous thrombosis, angina including unstable angina, coronaryplaque inflammation, bacterial-induced inflammation includingChlamydia-induced inflammation, viral induced inflammation, andinflammation associated with surgical procedures such as vasculargrafting including coronary artery bypass surgery, revascularizationprocedures including angioplasty, stent placement, endarterectomy, orother invasive procedures involving arteries, veins and capillaries.

[0220] Such compositions are useful in treatment of angiogenesis-relateddisorders in a subject, for example to inhibit tumor angiogenesis. Suchcompositions are useful in treatment of neoplasia, including metastasis;ophthalmological conditions such as corneal graft rejection, ocularneovascularization, retinal neovascularization includingneovascularization following injury or infection, diabetic retinopathy,macular degeneration, retrolental fibroplasia and neovascular glaucoma;ulcerative diseases such as gastric ulcer; pathological, butnon-malignant, conditions such as hemangiomas, including infantilehemaginomas, angiofibroma of the nasopharynx and avascular necrosis ofbone; and disorders of the female reproductive system such asendometriosis.

[0221] Such compositions are useful in prevention and treatment ofbenign and malignant tumors and neoplasia including cancer, such ascolorectal cancer, brain cancer, bone cancer, epithelial cell-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer, stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,cervical cancer, lung cancer, breast cancer, skin cancer such assquamous cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body. Neoplasias for which compositions of the inventionare contemplated to be particularly useful are gastrointestinal cancer,Barrett's esophagus, liver cancer, bladder cancer, pancreatic cancer,ovarian cancer, prostate cancer, cervical cancer, lung cancer, breastcancer and skin cancer. Such compositions can also be used to treatfibrosis that occurs with radiation therapy. Such compositions can beused to treat subjects having adenomatous polyps, including those withfamilial adenomatous polyposis (FAP). Additionally, such compositionscan be used to prevent polyps from forming in patients at risk of FAP.

[0222] Such compositions inhibit prostanoid-induced smooth musclecontraction by inhibiting synthesis of contractile prostanoids and hencecan be of use in treatment of dysmenorrhea, premature labor, asthma andeosinophil-related disorders. They also can be of use for decreasingbone loss particularly in postmenopausal women (i.e., treatment ofosteoporosis), and for treatment of glaucoma.

[0223] Because of the rapid onset of therapeutic effect that can beexhibited by compositions of the invention, these compositions haveparticular advantages over prior formulations for treatment of acuteCOX-2 mediated disorders, especially for relief of pain, for example inheadache, including sinus headache and migraine.

[0224] Preferred uses for compositions of the present invention are fortreatment of rheumatoid arthritis and osteoarthritis, for painmanagement generally (particularly post-oral surgery pain, post-generalsurgery pain, post-orthopedic surgery pain, and acute flares ofosteoarthritis), for prevention and treatment of headache and migraine,for treatment of Alzheimer's disease, and for colon cancerchemoprevention.

[0225] For treatment of rheumatoid arthritis or osteoarthritis, suchcompositions of the invention can be used to provide a daily dosage ofcelecoxib of about 50 mg to about 1000 mg, preferably about 100 mg toabout 600 mg, more preferably about 150 mg to about 500 mg, still morepreferably about 175 mg to about 400 mg, for example about 200 mg. Adaily dose of celecoxib of about 0.7 to about 13 mg/kg body weight,preferably about 1.3 to about 8 mg/kg body weight, more preferably about2 to about 6.7 mg/kg body weight, and still more preferably about 2.3 toabout 5.3 mg/kg body weight, for example about 2.7 mg/kg body weight, isgenerally appropriate when administered in a composition of theinvention. The daily dose can be administered in one to about four dosesper day, preferably one or two doses per day.

[0226] For treatment of Alzheimer's disease or cancer, such compositionsof the invention can be used to provide a daily dosage of celecoxib ofabout 50 mg to about 1000 mg, preferably about 100 mg to about 800 mg,more preferably about 150 mg to about 600 mg, and still more preferablyabout 175 mg to about 400 mg, for example about 400 mg. A daily dose ofabout 0.7 to about 13 mg/kg body weight, preferably about 1.3 to about10.7 mg/kg body weight, more preferably about 2 to about 8 mg/kg bodyweight, and still more preferably about 2.3 to about 5.3 mg/kg bodyweight, for example about 5.3 mg/kg body weight, is generallyappropriate when administered in a composition of the invention. Thedaily dose can be administered in one to about four doses per day,preferably one or two doses per day.

[0227] For pain management generally and specifically for treatment andprevention of headache and migraine, such compositions of the inventioncan be used to provide a daily dosage of celecoxib of about 50 mg toabout 1000 mg, preferably about 100 mg to about 600 mg, more preferablyabout 150 mg to about 500 mg, and still more preferably about 175 mg toabout 400 mg, for example about 200 mg. A daily dose of celecoxib ofabout 0.7 to about 13 mg/kg body weight, preferably about 1.3 to about 8mg/kg body weight, more preferably about 2 to about 6.7 mg/kg bodyweight, and still more preferably about 2.3 to about 5.3 mg/kg bodyweight, for example about 2.7 mg/kg body weight, is generallyappropriate when administered in a composition of the invention. Thedaily dose can be administered in one to about four doses per day.Administration at a rate of one 50 mg dose unit four times a day, one100 mg dose unit or two 50 mg dose units twice a day or one 200 mg doseunit, two 100 mg dose units or four 50 mg dose units once a day ispreferred.

[0228] For selective COX-2 inhibitory drugs other than celecoxib,appropriate doses can be selected by reference to the patent literaturecited hereinabove.

[0229] Besides being useful for human treatment, such compositions ofthe invention are useful for veterinary treatment of companion animals,exotic animals, farm animals, and the like, particularly mammals. Moreparticularly, such compositions of the invention are useful fortreatment of COX-2 mediated disorders in horses, dogs and cats.

[0230] This embodiment of the invention is further directed to atherapeutic method of treating a condition or disorder where treatmentwith a COX-2 inhibitory drug is indicated, the method comprising oraladministration of a composition of the invention to a subject in needthereof. The dosage regimen to prevent, give relief from, or amelioratethe condition or disorder preferably corresponds to once-a-day ortwice-a-day treatment, but can be modified in accordance with a varietyof factors. These include the type, age, weight, sex, diet and medicalcondition of the subject and the nature and severity of the disorder.Thus, the dosage regimen actually employed can vary widely and cantherefore deviate from the preferred dosage regimens set forth above.

[0231] Initial treatment can begin with a dose regimen as indicatedabove. Treatment is generally continued as necessary over a period ofseveral weeks to several months or years until the condition or disorderhas been controlled or eliminated. Subjects undergoing treatment with acomposition of the invention can be routinely monitored by any of themethods well known in the art to determine effectiveness of therapy.Continuous analysis of data from such monitoring permits modification ofthe treatment regimen during therapy so that optimally effective dosesare administered at any point in time, and so that the duration oftreatment can be determined. In this way, the treatment regimen anddosing schedule can be rationally modified over the course of therapy sothat the lowest amount of the composition exhibiting satisfactoryeffectiveness is administered, and so that administration is continuedonly for so long as is necessary to successfully treat the condition ordisorder.

[0232] Compositions of the present embodiment can be used in combinationtherapies with opioids and other analgesics, including narcoticanalgesics, Mu receptor antagonists, Kappa receptor antagonists,non-narcotic (i.e. non-addictive) analgesics, monoamine uptakeinhibitors, adenosine regulating agents, cannabinoid derivatives,Substance P antagonists, neurokinin-1 receptor antagonists and sodiumchannel blockers, among others. Preferred combination therapies compriseuse of a composition of the invention with one or more compoundsselected from aceclofenac, acemetacin, e-acetamidocaproic acid,acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid(aspirin), S-adenosylmethionine, alclofenac, alfentanil, allylprodine,alminoprofen, aloxiprin, alphaprodine, aluminum bis(acetylsalicylate),amfenac, aminochlorthenoxazin, 3-amino-4-hydroxybutyric acid,2-amino-4-picoline, aminopropylon, aminopyrine, amixetrine, ammoniumsalicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine,antipyrine salicylate, antrafenine, apazone, bendazac, benorylate,benoxaprofen, benzpiperylon, benzydamine, benzylmorphine, bermoprofen,bezitramide, α-bisabolol, bromfenac, p-bromoacetanilide,5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic acid,bucolome, bufexamac, bumadizon, buprenorphine, butacetin, butibufen,butophanol, calcium acetylsalicylate, carbamazepine, carbiphene,carprofen, carsalam, chlorobutanol, chlorthenoxazin, choline salicylate,cinchophen, cinmetacin, ciramadol, clidanac, clometacin, clonitazene,clonixin, clopirac, clove, codeine, codeine methyl bromide, codeinephosphate, codeine sulfate, cropropamide, crotethamide, desomorphine,dexoxadrol, dextromoramide, dezocine, diampromide, diclofenac sodium,difenamizole, difenpiramide, diflunisal, dihydrocodeine,dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminumacetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol,droxicam, emorfazone, enfenamic acid, epirizole, eptazocine, etersalate,ethenzamide, ethoheptazine, ethoxazene, ethylmethylthiambutene,ethylmorphine, etodolac, etofenamate, etonitazene, eugenol, felbinac,fenbufen, fenclozic acid, fendosal, fenoprofen, fentanyl, fentiazac,fepradinol, feprazone, floctafenine, flufenamic acid, flunoxaprofen,fluoresone, flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisicacid, glafenine, glucametacin, glycol salicylate, guaiazulene,hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,ibuproxam, imidazole salicylate, indomethacin, indoprofen, isofezolac,isoladol, isomethadone, isonixin, isoxepac, isoxicam, ketobemidone,ketoprofen, ketorolac, p-lactophenetide, lefetamine, levorphanol,lofentanil, lonazolac, lornoxicam, loxoprofen, lysine acetylsalicylate,magnesium acetylsalicylate, meclofenamic acid, mefenamic acid,meperidine, meptazinol, mesalamine, metazocine, methadone hydrochloride,methotrimeprazine, metiazinic acid, metofoline, metopon, mofebutazone,mofezolac, morazone, morphine, morphine hydrochloride, morphine sulfate,morpholine salicylate, myrophine, nabumetone, nalbuphine, 1-naphthylsalicylate, naproxen, narceine, nefopam, nicomorphine, nifenazone,niflumic acid, nimesulide, 5′-nitro-2′-propoxyacetanilide,norlevorphanol, normethadone, normorphine, norpipanone, olsalazine,opium, oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,oxyphenbutazone, papaveretum, paranyline, parsalmide, pentazocine,perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridinehydrochloride, phenocoll, phenoperidine, phenopyrazone, phenylacetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,piketoprofen, piminodine, pipebuzone, piperylone, piprofen, pirazolac,piritramide, piroxicam, pranoprofen, proglumetacin, proheptazine,promedol, propacetamol, propiram, propoxyphene, propyphenazone,proquazone, protizinic acid, ramifenazone, remifentanil, rimazoliummetilsulfate, salacetamide, salicin, salicylamide, salicylamide o-aceticacid, salicylsulfuric acid, salsalte, salverine, simetride, sodiumsalicylate, sufentanil, sulfasalazine, sulindac, superoxide dismutase,suprofen, suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide, tilidine,tinoridine, tolfenamic acid, tolmetin, tramadol, tropesin, viminol,xenbucin, ximoprofen, zaltoprofen and zomepirac (see The Merck Index,12th Edition (1996), Therapeutic Category and Biological Activity Index,lists therein headed “Analgesic”, “Anti-inflammatory” and“Antipyretic”).

[0233] Particularly preferred combination therapies comprise use of acomposition of this embodiment with an opioid compound, moreparticularly where the opioid compound is codeine, meperidine, morphineor a derivative thereof.

[0234] Combination therapy herein includes administration (to onesubject) of a single composition which itself comprises two or moredifferent drugs (e.g. co-formulated). Where a selective COX-2 inhibitorydrug is co-formulated with a second drug, for example an opioid drug,the second drug can be formulated in immediate-release, rapid-onset,sustained-release or dual-release form.

[0235] Combination therapy herein also includes separateco-administration (to one subject) of two or more different drugs, forexample each of which is present in an individual composition.Co-administration herein preferably means that each drug ordrug-containing composition to be co-administered is administered atrelative times which times are selected such that each drug hastherapeutically effectiveness for at least a period of time during whichthe other drug(s) being co-administered are therapeutically effective.

[0236] It is contemplated that each drug or drug-containing compositionwhich is to be co-administered will be administered to the subjectwithin a period of about 5 hours, more preferably within a period ofabout 2 hours, still more preferably within a period of about 1 hour,and still more preferably at substantially the same time. Relativeadministration times for two or more drugs or drug-containingcompositions which are to be co-administered will depend on, among otherfactors, the relative therapeutic onset-time of each drug or drugcontaining composition.

[0237] In an embodiment of the invention, particularly where the COX-2mediated condition is headache or migraine, the present selective COX-2inhibitory drug composition is administered in combination therapy witha vasomodulator, preferably a xanthine derivative having vasomodulatoryeffect, more preferably an alkylxanthine compound.

[0238] Combination therapies wherein an alkylxanthine compound isco-administered with a selective COX-2 inhibitory drug composition asprovided herein are embraced by the present embodiment of the inventionwhether or not the alkylxanthine is a vasomodulator and whether or notthe therapeutic effectiveness of the combination is to any degreeattributable to a vasomodulatory effect. The term “alkylxanthine” hereinembraces xanthine derivatives having one or more C₁₋₄ alkyl, preferablymethyl, substituents, and pharmaceutically acceptable salts of suchxanthine derivatives. Dimethylxanthines and trimethylxanthines,including caffeine, theobromine and theophylline, are especiallypreferred. Most preferably, the alkylxanthine compound is caffeine.

[0239] The total and relative dosage amounts of the selective COX-2inhibitory drug and of the vasomodulator or alkylxanthine are selectedto be therapeutically and/or prophylactically effective for relief ofpain associated with the headache or migraine. Suitable dosage amountswill depend on the particular selective COX-2 inhibitory drug and theparticular vasomodulator or alkylxanthine selected. For example, in acombination therapy with celecoxib and caffeine, typically the celecoxibwill be administered in a daily dosage amount of about 50 mg to about1000 mg, preferably about 100 mg to about 600 mg, and the caffeine in adaily dosage amount of about 1 mg to about 500 mg, preferably about 10mg to about 400 mg, more preferably about 20 mg to about 300 mg.

[0240] The vasomodulator or alkylxanthine component of the combinationtherapy can be administered in any suitable dosage form by any suitableroute, preferably orally. The vasomodulator or alkylxanthine canoptionally be coformulated with the selective COX-2 inhibitory drug in asingle oral dosage form. Thus a composition of the invention optionallycomprises both an selective COX-2 inhibitory drug and a vasomodulator oralkylxanthine compound such as caffeine, in total and relative amountsconsistent with the dosage amounts set out hereinabove.

[0241] The phrase “in total and relative amounts effective to relievepain”, with respect to amounts of a selective COX-2 inhibitory drug anda vasomodulator or alkylxanthine in a composition of the presentembodiment, means that these amounts are such that (a) together thesecomponents are effective to relieve pain, and (b) each component is orwould be capable of contribution to a pain-relieving effect if the othercomponent is or were not present in so great an amount as to obviatesuch contribution.

[0242] Nanoparticles comprising or consisting essentially of a selectiveCOX-2 inhibitory drug of low water solubility can be prepared accordingto any process previously applied to preparation of other poorly watersoluble drugs in nanoparticulate form. Suitable processes, withoutrestriction, are illustratively disclosed for such other drugs inpatents and publications listed below and incorporated herein byreference.

[0243] U.S. Pat. No. 4,826,689 to Violanto & Fischer.

[0244] Above-cited U.S. Pat. No. 5,145,684.

[0245] U.S. Pat. No. 5,298,262 to Na & Rajagopalan.

[0246] U.S. Pat. No. 5,302,401 to Liversidge et al.

[0247] U.S. Pat. No. 5,336,507 to Na & Rajagopalan.

[0248] U.S. Pat. No. 5,340,564 to Illig & Sarpotdar.

[0249] U.S. Pat. No. 5,346,702 to Na & Rajagopalan.

[0250] U.S. Pat. No. 5,352,459 to Hollister et al.

[0251] U.S. Pat. No. 5,354,560 to Lovrecich.

[0252] Above-cited U.S. Pat. No. 5,384,124.

[0253] U.S. Pat. No. 5,429,824 to June.

[0254] U.S. Pat. No. 5,503,723 to Ruddy et al.

[0255] U.S. Pat. No. 5,510,118 to Bosch et al.

[0256] U.S. Pat. No. 5,518,187 to Bruno et al.

[0257] U.S. Pat. No. 5,518,738 to Eickhoff et al.

[0258] U.S. Pat. No. 5,534,270 to De Castro.

[0259] U.S. Pat. No. 5,536,508 to Canal et al.

[0260] U.S. Pat. No. 5,552,160 to Liversidge et al.

[0261] U.S. Pat. No. 5,560,931 to Eickhoff et al.

[0262] U.S. Pat. No. 5,560,932 to Bagchi et al.

[0263] U.S. Pat. No. 5,565,188 to Wong et al.

[0264] U.S. Pat. No. 5,569,448 to Wong et al.

[0265] U.S. Pat. No. 5,571,536 to Eickhoff et al.

[0266] U.S. Pat. No. 5,573,783 to Desieno & Stetsko.

[0267] U.S. Pat. No. 5,580,579 to Ruddy et al.

[0268] U.S. Pat. No. 5,585,108 to Ruddy et al.

[0269] U.S. Pat. No. 5,587,143 to Wong.

[0270] U.S. Pat. No. 5,591,456 to Franson et al.

[0271] U.S. Pat. No. 5,622,938 to Wong.

[0272] U.S. Pat. No. 5,662,883 to Bagchi et al.

[0273] U.S. Pat. No. 5,665,331 to Bagchi et al.

[0274] U.S. Pat. No. 5,718,919 to Ruddy et al.

[0275] U.S. Pat. No. 5,747,001 to Wiedmann et al.

[0276] Above-cited International Patent Publication No. WO 93/25190.

[0277] International Patent Publication No. WO 96/24336.

[0278] International Patent Publication No. WO 97/14407.

[0279] International Patent Publication No. WO 98/35666.

[0280] International Patent Publication No. WO 99/65469.

[0281] International Patent Publication No. WO 00/18374.

[0282] International Patent Publication No. WO 00/27369.

[0283] International Patent Publication No. WO 00/30615.

[0284] One of ordinary skill in the art will readily adapt the processestherein described to preparation of a poorly water soluble selectiveCOX-2 inhibitory drug in nanoparticulate form.

[0285] In one embodiment of the invention, nanoparticles of a selectiveCOX-2 inhibitory drug are prepared by a milling process, preferably awet milling process in presence of a surface modifying agent thatinhibits aggregation and/or crystal growth of nanoparticles oncecreated. In another embodiment of the invention, nanoparticles of aselective COX-2 inhibitory drug are prepared by a precipitation process,preferably a process of precipitation in an aqueous medium from asolution of the drug in a non-aqueous solvent. The non-aqueous solventcan be a liquefied, e.g., supercritical, gas under pressure.Illustrative examples of these and other processes for preparingnanoparticles of a selective COX-2 inhibitory drug are presented withgreater particularity below.

[0286] In one particular embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) dispersing a selectiveCOX-2 inhibitory drug and a surface modifying agent in a liquiddispersion medium; and (b) wet milling the resulting drug dispersion inpresence of grinding media to result in crystalline nanoparticles of thedrug having the surface modifying agent adsorbed on the surface thereofin an amount sufficient to maintain a weight average particle size ofless than about 400 nm, substantially as disclosed in above-cited U.S.Pat. No. 5,145,684. The surface modifying agent inhibits aggregation ofthe nanoparticles and can be any of various polymers, low molecularweight oligomers, natural products, surfactants, etc. The nanoparticlesin this and related embodiments are referred to herein as being composedof a nanocrystalline drug/surface modifier complex.

[0287] In a related embodiment of the invention, a nanocrystallinedrug/surface modifier complex prepared as described above comprises apurified surface modifying agent, for example a purified polymericsurfactant, to prevent particle aggregation during a subsequentsterilization step, substantially as disclosed in above-cited U.S. Pat.No. 5,352,459.

[0288] In another related embodiment of the invention, a nanocrystallinedrug/surface modifier complex prepared as described above comprises as asurface modifying agent the surfactant p-isononylphenoxypoly(glycidol),substantially as disclosed in above-cited U.S. Pat. No. 5,340,564.

[0289] In another related embodiment of the invention, a nanocrystallinedrug/surface modifier complex prepared as described above is associatedwith an anionic or cationic cloud point modifier to increase the cloudpoint of the surface modifying agent, substantially as described inabove-cited U.S. Pat. No. 5,298,262 (cationic or anionic surfactant ascloud point modifier), U.S. Pat. No. 5,336,507 (charged phospholipid ascloud point modifier), or U.S. Pat. No. 5,346,702 (non-ionic cloud pointmodifier).

[0290] In another related embodiment of the invention, a nanocrystallinedrug/surface modifier complex prepared as described above furthercomprises a cryoprotectant, for example a carbohydrate or sugar alcohol,in an amount sufficient to permit the nanoparticles to be lyophilized,substantially as described in above-cited U.S. Pat. No. 5,302,401. Apreferred cryoprotectant of this embodiment is sucrose. The method ofmaking nanoparticles having a surface modifier adsorbed on the surfacethereof and a cryoprotectant associated therewith comprises contactingthe nanoparticles with the cryoprotectant for a time and underconditions sufficient to permit lyophilization of the nanoparticles.

[0291] In another related embodiment of the invention, nanoparticulatedrug particles having a surface modifying agent adsorbed on the surfacethereof in an amount sufficient to maintain a weight average particlesize of less than about 400 nm are prepared by a process comprising thesteps of (a) dispersing the drug in a liquid dispersion medium whereinthe drug is insoluble; and (b) grinding the medium (e.g., in adispersion mill) in the presence of rigid grinding media, wherein pH ofthe medium is maintained within a range of about 2 to about 6,substantially as disclosed in above-cited U.S. Pat. No. 5,552,160.

[0292] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) providing a selectiveCOX-2 inhibitory drug substance; (b) depyrogenating rigid grindingmedia, for example in an oven at about 200° C. to about 300° C. forabout 6 to about 20 hours; mixing the drug substance and grinding mediatogether and autoclaving at about 100° C. to about 150° C. for about 10to about 60 minutes); and (c) adding a surface modifying agent (e.g.,selected from polymers, low molecular weight oligomers, natural productsand surfactants) to the resulting autoclaved drug substance followed bywet grinding to provide and maintain a weight average particle size ofless than about 400 nm, substantially as disclosed in above-cited U.S.Pat. No. 5,534,270.

[0293] In another related embodiment of the invention, nanoparticles areprepared by a process comprising contacting a selective COX-2 inhibitorydrug with a surface modifying agent (e.g., by adding the drug to aliquid medium comprising the surface modifying agent and wet grinding ina dispersion mill) for a time and under conditions sufficient to provideand maintain a weight average particle size of less than about 400 nm,substantially as described in above-cited U.S. Pat. No. 5,429,824. Inthis embodiment the surface modifying agent is a nonionic liquid polymerof the alkylaryl polyether alcohol type, for example tyloxapol.Optionally an additional surface modifying agent can be present.

[0294] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) forming a premix of aselective COX-2 inhibitory drug and a surface modifier (e.g., selectedfrom polymers, low molecular weight oligomers, surfactants, etc.) in aliquid dispersion medium (e.g., water, salt solution, ethanol, etc.);(b) transferring the premix to a microfluidizer having an interactionchamber capable of producing shear, impact, cavitation and attritionforces; (c) subjecting the premix to these forces at a temperature notexceeding about 40° C. and a fluid pressure of about 20,000 to about200,000 kPa by passing the premix through the interaction chamber toreduce the particle size of the drug and to obtain a homogeneous slurrythereof, (d) collecting the slurry from the interaction chamber into areceiving tank; (e) reintroducing the slurry into the interactionchamber to further reduce particle size; and (f) repeating thecollection and reintroduction steps until the weight average particlesize of the drug is less than about 400 nm, substantially as disclosedin above-cited U.S. Pat. No. 5,510,118.

[0295] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) milling (e.g., in adispersion mill), optionally in the presence of an oil, a selectiveCOX-2 inhibitory drug in the presence of surface modifying agents (e.g.,gelatin, casein, lecithin, polyvinylpyrrolidone, tyloxapol, poloxamers,other block polymers, etc.) substantially as disclosed in above-citedU.S. Pat. No. 5,560,931. In this embodiment, the drug particles have anon-crosslinked modifier adsorbed on the surface thereof, and aresuspended in an aqueous phase which is emulsified in a continuous oilphase. Weight average particle size is less than about 1000 nm. The oilphase can be oleic acid, as disclosed in above-cited U.S. Pat. No.5,571,536.

[0296] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) introducing aselective COX-2 inhibitory drug, a liquid medium, grinding media and asurface modifying agent into a grinding vessel; and (b) wet grinding toreduce the weight average particle size of the drug to less than about1000 nm, substantially as disclosed in above-cited U.S. Pat. No.5,565,188 (block copolymer as surface modifying agent containing one ormore polyoxyethylene blocks and one or more polyoxy(higher alkylene)blocks wherein at least some of the blocks are linked together by anoxymethylene linking group) and U.S. Pat. No. 5,587,143 (block copolymerof ethylene oxide and butylene oxide as surface modifying agent).

[0297] In another related embodiment of the invention, a composition isprovided comprising nanoparticulate selective COX-2 inhibitory drugparticles having a block copolymer linked to at least one anionic groupas a surface modifying agent adsorbed on the surface thereof. Thecomposition is prepared by a process comprising the steps of (a)preparing the drug in particulate form, preferably at a particle sizeless than about 100 μm; (b) adding the drug to a liquid medium in whichit is essentially insoluble to form a premix; and (c) subjecting thepremix to mechanical means to reduce the average particle size in thepremix to less than about 1000 nm, substantially as disclosed inabove-cited U.S. Pat. No. 5,569,448. Preferably, the surface modifyingagent is present in the premix.

[0298] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) adding a selectiveCOX-2 inhibitory drug and a surface modifying agent (e.g., a stericstabilizer such as gelatin, casein, lecithin, gum acacia, cholesterol,tragacanth, sorbitan esters, polyethylene glycol, polyoxyethylene alkylesters, polyoxyethylene stearates, etc.) to a liquid in which the drugis insoluble to form a premix, and (b) subjecting the premix tomechanical means (e.g., in a dispersion mill) to reduce average particlesize to less than about 400 nm, substantially as disclosed inabove-cited U.S. Pat. No. 5,573,783.

[0299] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) dispersing a selectiveCOX-2 inhibitory drug and a surface active agent (e.g., poloxamershaving a molecular weight of about 1,000 to about 15,000 daltons,polyvinyl alcohol, polyvinylpyrrolidone, hydroxypropylmethylcellulose,and polyoxyethylene sorbitan monooleate) in a liquid dispersion mediumin which the drug is poorly soluble, then applying mechanical means(e.g., in a dispersion mill) to reduce drug particle size to less thanabout 400 nm, substantially as disclosed in above-cited U.S. Pat. No.5,585,108.

[0300] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) adding a selectiveCOX-2 inhibitory drug and hydroxypropylcellulose as a surface modifyingagent to a liquid medium in which the drug is essentially insoluble toform a premix, and employing mechanical means (e.g., in a dispersionmill) to reduce drug particle size to less than about 1000 nm,preferably less than about 400 nm, substantially as disclosed inabove-cited U.S. Pat. No. 5,591,456.

[0301] In another related embodiment of the invention, nanoparticles areprepared by a process as described herein that employs a surfacemodifying agent, the surface modifying agent being selected such thatthe resulting composition has a hydrophile-lipophile balance (HLB) ofabout 4 to about 9, substantially as disclosed in above-citedInternational Patent Publication No. WO 00/30615.

[0302] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) mixing a selectiveCOX-2 inhibitory drug with a support material, preferably a crosslinked,water-swellable polymer; (b) grinding the resulting mixture in agrinding chamber which is saturated with a solvent vapor (e.g., water,ethanol, isopropanol, chloroform, methanol, etc.); (c) drying the groundmixture under vacuum; and (d) sieving the dried ground mixture toeliminate any aggregates formed, substantially as disclosed inabove-cited U.S. Pat. No. 5,354,560.

[0303] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) forming a pastecomprising (i) nanoparticles of a selective COX-2 inhibitory drug, (ii)at least one thickening or binding agent (e.g., selected frompolypeptides, high molecular weight polymers, colloids, etc.) and/orextender, (iii) one or more stabilizing agents to prevent settlingand/or rising to the surface of the nanoparticles, and (iv) a suitableamount of water to adjust viscosity; and (b) lyophilizing the paste,substantially as disclosed in above-cited U.S. Pat. No. 5,384,124.

[0304] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) preparing aselective COX-2 inhibitory drug in particulate form, preferably at aparticle size smaller than about 100 μm; (b) adding the prepared drug toa liquid medium (preferably comprising a surface modifying agent such asa hygroscopic sugar) in which the drug is essentially insoluble to forma premix; and (c) subjecting the premix to mechanical means to reducethe average particle size in the premix to less than about 1000 nm,substantially as disclosed in above-cited U.S. Pat. No. 5,518,738.Preferably, polyvinylpyrrolidone and/or a wetting agent, e.g., sodiumlauryl sulfate, are also present in the premix. Compositions prepared bythis process preferably have a film adsorbed on the surface of thenanoparticles comprising a polyvinylpyrrolidone, a hygroscopic sugar andsodium lauryl sulfate.

[0305] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) co-solubilizingone or more polymeric constituents including, for example, abiodegradable polymer (e.g., polylactic acid, polyglycolic acid orco-polymers thereof, polyhydroxybutyric acid, polycaprolactone,polyorthoesters, etc.), a polysaccharide jellifying and/or bioadhesivepolymer, and/or an amphiphilic polymer (e.g. polyethylene glycol,polyvinylpyrrolidone or polyvinyl alcohol) together with an agentmodifying interface properties to form a polymer mixture, optionally inthe presence of one or more solvents; (b) dissolving or suspending aselective COX-2 inhibitory drug in the polymer mixture; and (c) formingparticles consisting of the polymers, the agent modifying the interfaceproperties and the drug by a technique of emulsion, extrusion, spraydrying or spray congealing, substantially as disclosed in above-citedU.S. Pat. No. 5,536,508. Nanoparticles prepared by this processpreferably have a weight average particle size of about 0.1 μm to about150 μm.

[0306] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) preparing asolution of a selective COX-2 inhibitory drug in a water-miscibleorganic solvent; (b) infusing an aqueous precipitating liquid (e.g.,water, solution of mineral salt, or surfactant solution) into thesolution to produce a suspension of precipitated, amorphous, solid drugin the form of non-aggregated particles; and (c) separating theparticles from the precipitating liquid and washing in an aqueouswashing liquid, substantially as disclosed in above-cited U.S. Pat. No.4,826,689.

[0307] In another particular embodiment of the invention, nanoparticlesare prepared by a process comprising the steps of (a) dissolving aselective COX-2 inhibitory drug in an aqueous base (e.g., NaOH, KOH,CsOH, etc.) with stirring to form a solution; (b) adding a surfacemodifier (e.g., various polymers, surfactants, low molecular weightoligomers, etc.) to form a clear solution; and (c) neutralizing theclear solution with stirring and with an appropriate acid solution(e.g., HCl, HNO₃, HClO₄, H₂SO₄, formic acid, propionic acid, aceticacid, butyric acid, etc.), substantially as disclosed in above-citedU.S. Pat. Nos. 5,560,932 and 5,580,579.

[0308] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) dissolving a selectiveCOX-2 inhibitory drug in a liquid medium base (e.g., NaOH, KOH, CsOH,trialkylamines, pyridine, etc.) comprising a non-toxic solvent in whichthe drug is poorly soluble to form a solution; (b) adding an aqueoussolution of one or more surface modifying agents (e.g., anionic ornonionic surfactants, polymeric or oligomeric substances); and (c)neutralizing the resulting alkaline solution with an acid (e.g., HCl,HNO₃, HClO₄, H₂SO₄, formic acid, propionic acid, acetic acid, butyricacid, etc.), to form a dispersion, preferably having a Z-averageparticle diameter of less than about 100 nm as measured by photoncorrelation spectroscopy, substantially as disclosed in above-cited U.S.Pat. No. 5,662,883.

[0309] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) dissolving a selectiveCOX-2 inhibitory drug and a crystal growth modifier (i.e., a compoundthat is substantially isostructural to the drug) in an aqueous base(e.g., NaOH, KOH, CsOH, trialkylamines, pyridine, etc.) to form asolution; (b) adding an aqueous solution of one or more surfacemodifying agents (e.g., a mixture of anionic surfactant, nonionicsurfactant, polymeric substance and oligomeric substance); andneutralizing the resulting alkaline solution with an acid (e.g., HCl,HNO₃, HClO₄, H₂SO₄, formic acid, propionic acid, acetic acid, butyricacid, etc.), to form a dispersion, preferably wherein the drug particleshave a Z-average particle diameter of less than about 400 nm as measuredby photon correlation spectroscopy, substantially as disclosed inabove-cited U.S. Pat. No. 5,665,331.

[0310] In another particular embodiment of the invention, nanoparticleshaving a weight average particle size of less than about 400 nm areprepared from a dispersion comprising a first particle distribution of aselective COX-2 inhibitory drug together with a surface modifying agentsuch as polysulfated tyloxapol by a process comprising the steps of (a)placing the dispersion between a first electrode and a second electrode;and (b) removing a portion of the dispersion at a position between thefirst electrode and the second electrode, this portion of the dispersionhaving a second particle size distribution that is smaller than thefirst particle distribution, substantially as disclosed in above-citedU.S. Pat. No. 5,503,723.

[0311] In another particular embodiment of the invention, nanoparticleshaving a weight average particle size of up to about 300 nm are preparedby a process comprising the steps of (a) dissolving a selective COX-2inhibitory drug in a solvent to form a solution; and (b) spraying thesolution into a liquefied gas or supercritical fluid in presence of asurface modifying agent dispersed or dissolved in an aqueous phase,substantially as disclosed in above-cited International PatentPublication No. WO 97/14407.

[0312] In another related embodiment of the invention, nanoparticleshaving a weight average particle size of up to about 300 nm are preparedby a process comprising the steps of (a) dissolving a selective COX-2inhibitory drug in a liquefied gas or supercritical fluid to form asolution; (b) preparing an aqueous phase containing a surface modifyingagent; and (c) spraying the solution into the aqueous phase,substantially as disclosed in the same above-cited International PatentPublication No. WO 97/14407.

[0313] In another related embodiment of the invention, nanoparticles areprepared by a process comprising the steps of (a) dissolving a selectiveCOX-2 inhibitory drug and a surface modifying agent in a liquefied gasor supercritical fluid to form a solution; and (b) expanding thesolution into an aqueous medium, substantially as disclosed inabove-cited International Patent Publication No. WO 99/13755.

[0314] Excipients included in a composition of the invention can besolids or liquids or both. Compositions of the invention containingexcipients can be prepared by any technique of pharmacy that comprisesadmixing the excipients with a selective COX-2 inhibitory drug that hasbeen at least partially pre-prepared, optionally together with one ormore excipients, in nanoparticulate form as indicated above.

[0315] Compositions suitable for buccal or sublingual administrationinclude, for example, lozenges comprising the selective COX-2 inhibitorydrug in a flavored base, such as sucrose and acacia or tragacanth, andpastilles comprising the drug in an inert base such as gelatin andglycerin or sucrose and acacia.

[0316] Liquid dosage forms for oral administration includepharmaceutically acceptable suspensions, syrups, and elixirs containinginert diluents commonly used in the art, such as water. Suchcompositions may also comprise, for example, wetting agents, emulsifyingand suspending agents, and sweetening, flavoring, and perfuming agents.

[0317] Solid unit dosage forms for oral administration contain theselective COX-2 inhibitory drug in nanoparticulate form together withexcipients and are most conveniently formulated as tablets or capsules.Non-limiting examples follow of excipients that can be used to preparepharmaceutical compositions of the invention.

[0318] Compositions of the invention optionally comprise one or morepharmaceutically acceptable diluents as excipients. Suitable diluentsillustratively include, either individually or in combination, lactose,including anhydrous lactose and lactose monohydrate; starches, includingdirectly compressible starch and hydrolyzed starches (e.g., Celutab™ andEmdex™); mannitol; sorbitol; xylitol; dextrose (e.g., Cerelose™ 2000)and dextrose monohydrate; dibasic calcium phosphate dihydrate;sucrose-based diluents; confectioner's sugar; monobasic calcium sulfatemonohydrate; calcium sulfate dihydrate; granular calcium lactatetrihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose;celluloses including microcrystalline cellulose, food grade sources ofα- and amorphous cellulose (e.g., Rexcel™) and powdered cellulose;calcium carbonate; glycine; bentonite; polyvinylpyrrolidone; and thelike. Such diluents, if present, constitute in total about 5% to about99%, preferably about 10% to about 85%, and more preferably about 20% toabout 80%, of the total weight of the composition. The diluent ordiluents selected preferably exhibit suitable flow properties and, wheretablets are desired, compressibility.

[0319] Lactose and microcrystalline cellulose, either individually or incombination, are preferred diluents. Both diluents are chemicallycompatible with celecoxib. The use of extragranular microcrystallinecellulose (that is, microcrystalline cellulose added to a wet granulatedcomposition after a drying step) can be used to improve hardness (fortablets) and/or disintegration time. Lactose, especially lactosemonohydrate, is particularly preferred. Lactose typically providescompositions having suitable release rates of celecoxib, stability,pre-compression flowability, and/or drying properties at a relativelylow diluent cost. It provides a high density substrate that aidsdensification during granulation (where wet granulation is employed) andtherefore improves blend flow properties.

[0320] Compositions of the invention optionally comprise one or morepharmaceutically acceptable disintegrants as excipients, particularlyfor tablet formulations. Suitable disintegrants include, eitherindividually or in combination, starches, including sodium starchglycolate (e.g., Explotab™ of PenWest) and pregelatinized corn starches(e.g., National™ 1551, National™ 1550, and Colocorn™ 1500), clays (e.g.,Veegum™ HV), celluloses such as purified cellulose, microcrystallinecellulose, methylcellulose, carboxymethylcellulose and sodiumcarboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-Sol™ of FMC),alginates, crospovidone, and gums such as agar, guar, locust bean,karaya, pectin and tragacanth gums.

[0321] Disintegrants may be added at any suitable step during thepreparation of the composition, particularly prior to granulation orduring a lubrication step prior to compression. Such disintegrants, ifpresent, constitute in total about 0.2% to about 30%, preferably about0.2% to about 10%, and more preferably about 0.2% to about 5%, of thetotal weight of the composition.

[0322] Croscarmellose sodium is a preferred disintegrant for tablet orcapsule disintegration, and, if present, preferably constitutes about0.2% to about 110%, more preferably about 0.2% to about 7%, and stillmore preferably about 0.2% to about 5%, of the total weight of thecomposition. Croscarmellose sodium confers superior intragranulardisintegration capabilities to granulated compositions of the presentinvention.

[0323] Compositions of the invention optionally comprise one or morepharmaceutically acceptable binding agents or adhesives as excipients,particularly for tablet formulations. Such binding agents and adhesivespreferably impart sufficient cohesion to the powder being tableted toallow for normal processing operations such as sizing, lubrication,compression and packaging, but still allow the tablet to disintegrateand the composition to be absorbed upon ingestion. Suitable bindingagents and adhesives include, either individually or in combination,acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but notlimited to, pregelatinized starches (e.g., National™ 1511 and National™1500); celluloses such as, but not limited to, methylcellulose andcarmellose sodium (e.g., Tylose™); alginic acid and salts of alginicacid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids;bentonites; povidone, for example povidone K-15, K-30 and K-29/32;polymethacrylates; HPMC; hydroxypropylcellulose (e.g., Klucel™); andethylcellulose (e.g., Ethocel™). Such binding agents and/or adhesives,if present, constitute in total about 0.5% to about 25%, preferablyabout 0.75% to about 15%, and more preferably about 1% to about 10%, ofthe total weight of the composition.

[0324] Compositions of the invention optionally comprise one or morepharmaceutically acceptable wetting agents as excipients. Such wettingagents are preferably selected to maintain the selective COX-2inhibitory drug in close association with water, a condition that isbelieved to improve bioavailability of the composition.

[0325] Non-limiting examples of surfactants that can be used as wettingagents in compositions of the invention include quaternary ammoniumcompounds, for example benzalkonium chloride, benzethonium chloride andcetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylenealkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefossé), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, preferably about 0.4% to about 10%, and morepreferably about 0.5% to about 5%, of the total weight of thecomposition.

[0326] Wetting agents that are anionic surfactants are preferred. Sodiumlauryl sulfate is a particularly preferred wetting agent. Sodium laurylsulfate, if present, constitutes about 0.25% to about 7%, morepreferably about 0.4% to about 4%, and still more preferably about 0.5%to about 2%, of the total weight of the composition.

[0327] Compositions of the invention optionally comprise one or morepharmaceutically acceptable lubricants (including anti-adherents and/orglidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behapate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium, calcium andsodium stearates; hydrogenated vegetable oils (e.g., Sterotex™);colloidal silica; talc; waxes; boric acid; sodium benzoate; sodiumacetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g.,Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodium laurylsulfate; and magnesium lauryl sulfate. Such lubricants, if present,constitute in total about 0.1% to about 10%, preferably about 0.2% toabout 8%, and more preferably about 0.25% to about 5%, of the totalweight of the composition.

[0328] Magnesium stearate is a preferred lubricant used, for example, toreduce friction between the equipment and granulated mixture duringcompression of tablet formulations.

[0329] Suitable anti-adherents include talc, cornstarch, DL-leucine,sodium lauryl sulfate and metallic stearates. Talc is a preferredanti-adherent or glidant used, for example, to reduce formulationsticking to equipment surfaces and also to reduce static in the blend.Talc, if present, constitutes about 0.1% to about 10%, more preferablyabout 0.25% to about 5%, and still more preferably about 0.5% to about2%, of the total weight of the composition.

[0330] Other excipients such as colorants, flavors and sweeteners areknown in the pharmaceutical art and can be used in compositions of thepresent invention. Tablets can be coated, for example with an entericcoating, or uncoated. Compositions of the invention can furthercomprise, for example, buffering agents.

[0331] Optionally, one or more effervescent agents can be used asdisintegrants and/or to enhance organoleptic properties of compositionsof the invention. When present in compositions of the invention topromote dosage form disintegration, one or more effervescent agents arepreferably present in a total amount of about 30% to about 75%, andpreferably about 45% to about 70%, for example about 60%, by weight ofthe composition.

[0332] In one embodiment of the invention, the composition is in theform of unit dose capsules or tablets and comprises a partially orwholly nanoparticulate selective COX-2 inhibitor, illustrativelycelecoxib, in a desired amount together with one or more excipientsselected from the group consisting of pharmaceutically acceptablediluents, disintegrants, binding agents, wetting agents and lubricants.More preferably, the composition comprises one or more excipientsselected from the group consisting of lactose (most preferably lactosemonohydrate), sodium lauryl sulfate, polyvinylpyrrolidone,croscarmellose sodium, magnesium stearate and microcrystallinecellulose. Still more preferably, the composition comprises lactosemonohydrate and croscarmellose sodium. Even more preferably, such acomposition further comprises one or more of the carrier materialssodium lauryl sulfate, magnesium stearate and microcrystallinecellulose.

[0333] Excipients for capsule and tablet compositions of the inventionare preferably selected to provide a disintegration time of less thanabout 30 minutes, preferably about 25 minutes or less, more preferablyabout 20 minutes or less, and still more preferably about 15 minutes orless, in a standard disintegration assay.

[0334] Illustratively for tablet formulations, a complete blend ofingredients in an amount sufficient to make a uniform batch of tabletsis subjected to tableting in a conventional production scale tabletingmachine at normal compression pressure (for example, applying a force ofabout 1 kN to about 50 kN in a typical tableting die). Any tablethardness convenient with respect to handling, manufacture, storage andingestion can be obtained. For 100 mg tablets, hardness is preferably atleast 4 kP, more preferably at least about 5 kP, and still morepreferably at least about 6 kP. For 200 mg tablets, hardness ispreferably at least 7 kP, more preferably at least about 9 kP, and stillmore preferably at least about 11 kP. The mixture, however, is not to becompressed to such a degree that there is subsequent difficulty inachieving hydration when exposed to gastric fluid.

[0335] Tablet friability is preferably less than about 1.0%, morepreferably less than 0.8%, and still more preferably less than about0.5% in a standard test.

[0336] Wet granulation, dry granulation or direct compression orencapsulation methods can be employed to prepare tablet or capsulecompositions of the invention.

[0337] Although unit dose capsule and tablet compositions of theinvention can be prepared, for example, by direct encapsulation ordirect compression, they are preferably wet granulated prior toencapsulation or compression. Wet granulation, among other effects,densities milled compositions resulting in improved flow properties,improved compression characteristics and easier metering or weightdispensing of the compositions for encapsulation or tableting. Thesecondary particle size resulting from granulation (i.e., granule size)is not narrowly critical, it being important only that the averagegranule size preferably is such as to allow for convenient handling andprocessing and, for tablets, to permit the formation of a directlycompressible mixture that forms pharmaceutically acceptable tablets.

[0338] In an illustrative wet granulation process, any portion of thedrug that is not to be included in nanoparticulate form (if desired,together with one or more carrier materials) is initially milled ormicronized to a desired range of particle sizes greater than 1 μm.Although various conventional mills or grinders can be used, impactmilling such as pin milling of the drug provides improved blenduniformity to the final composition relative to other types of milling.Cooling of the material being milled, for example, using liquidnitrogen, may be necessary during milling to avoid heating the drug toundesirable temperatures. The D₉₀ particle size during this milling stepis preferably reduced to less than about 25 μm.

[0339] The milled or micronized drug, if any, is then blended with thedesired amount of nanoparticulate drug, prepared as indicatedhereinabove to provide a partially or wholly nanoparticulate drugsubstance. Simultaneously or thereafter, the drug substance is blended,for example in a high shear mixer/granulator, planetary mixer,twin-shell blender or sigma mixer, with one or more excipients,including excipients that have been milled together with the celecoxibor are present in the nanoparticles, to form a dry powder mixture.Typically, the drug substance is blended with one or more diluent(s),disintegrant(s) and/or binding agent(s) and, optionally, one or morewetting agent(s) in this step, but alternatively all or a portion of oneor more of the excipients can be added in a later step. For example, intablet formulations where croscarmellose sodium is employed as adisintegrant, it has been discovered that addition of a portion of thecroscarmellose sodium during the blending step (providing intragranularcroscarmellose sodium) and addition of the remaining portion after thedrying step discussed below (providing extragranular croscarmellosesodium) can improve disintegration of the tablets produced. In thissituation, preferably about 60% to about 75% of the croscarmellosesodium is added intragranularly and about 25% to about 40% of thecroscarmellose sodium is added extragranularly. Similarly, for tabletformulations it has been discovered that addition of microcrystallinecellulose after the drying step below (extragranular microcrystallinecellulose) can improve compressibility of the granules and hardness oftablets prepared from the granules.

[0340] This blending step of the process preferably comprises blendingof drug substance, lactose, polyvinylpyrrolidone and croscarmellosesodium. It has been discovered that a blending time as short as threeminutes can provide a dry powder mixture having a sufficiently uniformdistribution of the drug to provide a commercially acceptable tablet.

[0341] Water, preferably purified water, is then added to the dry powdermixture and the mixture is blended for an additional period of time, toform a wet granulated mixture. Preferably a wetting agent is used, andthis is preferably first added to the water and mixed for at least 15minutes, preferably at least 20 minutes, prior to adding the water tothe dry powder mixture. The water can be added to the mixture at once,gradually over a period of time, or in several portions over a period oftime. The water is preferably added gradually over a period of time.Alternatively, the wetting agent can be added to the dry powder mixtureand water can then be added to the resulting mixture. An additionalperiod of mixing after water addition is complete is preferred to ensureuniform distribution of water in the mixture.

[0342] The wet granulated mixture is preferably then wet milled, forexample with a screening mill, to eliminate large agglomerates ofmaterial that form as a by-product of the wet granulation operation. Ifnot removed, these agglomerates would prolong the subsequent dryingoperation and increase variation with respect to moisture control.

[0343] The wet granulated or wet milled mixture is then dried, forexample, in an oven or a fluid bed dryer, preferably a fluid bed drier,to form dry granules. If desired, the wet granulated mixture can beextruded or spheronized prior to drying. For the drying process,conditions such as inlet air temperature and drying time are adjusted toachieve the desired moisture content for the dry granules. It may bedesirable to combine two or more granulation sections for this dryingstep and subsequent processing steps.

[0344] To the extent necessary, the dry granules are then reduced insize in preparation for compression or encapsulation. Conventionalparticle size reduction equipment such as oscillators or impact mills(such as Fitz mills) can be employed.

[0345] A slight decrease in granule size has been observed as mixingtime increases for mixtures containing lower water amounts. It ishypothesized that where water concentration is too low to fully activatethe binding agent employed, cohesive forces between the primaryparticles within the granules are insufficient to survive the shearingforces generated by the mixing blades and granule size attrition ratherthan growth occurs. Conversely, increasing the amount of water to fullyactivate the binding agent allows cohesive forces between the primaryparticles to survive the shearing forces generated by the mixing bladesand granule growth rather than attrition occurs with increased mixingtime and/or water addition rate. Variation of the screen size of the wetmill tends to have a greater impact on the granule size than variationof the feed rate and/or mill speed.

[0346] The dry granules are then placed in a suitable blender, such as atwin-shell blender, and optionally a lubricant (such as magnesiumstearate) and any additional carrier materials are added (such asextragranular microcrystalline cellulose and/or extragranularcroscarmellose sodium in certain tablet formulations) to form a finalblended mixture. Where the diluents include microcrystalline cellulose,the addition of a portion of the microcrystalline cellulose during thisstep has been found to materially increase granule compressibility andtablet hardness. However, increasing the amount of magnesium stearateabove about 1% to about 2% tends to decrease tablet hardness andincrease friability and dissolution time.

[0347] This final blended mixture is then encapsulated (or, if tabletsare to be prepared, compressed into tablets of the desired weight andhardness using appropriately sized tooling). Conventional compressionand encapsulation techniques known in the art can be employed. Suitableresults are obtained for capsules by employing bed heights ranging fromabout 20 mm to about 60 mm, compaction settings ranging from about 0 toabout 5 mm, and speeds from about 60,000 capsules per hour to about130,000 capsules per hour. Slug formation can be minimized or eliminatedby using the lowest compaction setting at which capsule weight controlcan be maintained. Where coated tablets are desired, conventionalcoating techniques known in the art can be employed.

[0348] This combination of operations produces granules that are uniformin drug content at the unit dose level, that readily disintegrate, thatflow with sufficient ease so that weight variation can be reliablycontrolled during capsule filling or tableting, and that are denseenough in bulk so that the batch can be processed in the selectedequipment and individual doses fit into the specified capsules or tabletdies.

[0349] The present invention is also directed to use of compositions ofthe invention in preparation of medicaments useful in treatment and/orprophylaxis of COX-2 mediated conditions and disorders, in particularsuch conditions and disorders where rapid onset of therapeutic effect isdesired or required.

DESCRIPTION OF A PARTICULARLY PREFERRED EMBODIMENT

[0350] Patent and other literature relating to nanoparticulate drugcompositions teaches that, in general, the smaller the drug particlesize, the greater is the advantage in speed of onset of therapeuticeffect, or other pharmacodynamic benefit, obtained upon oraladministration. For example, at least the following patents proposereduction of particle size to about 400 nm or smaller.

[0351] Above-cited U.S. Pat. No. 5,145,684.

[0352] Above-cited U.S. Pat. No. 5,298,262.

[0353] Above-cited U.S. Pat. No. 5,302,401.

[0354] Above-cited U.S. Pat. No. 5,336,507.

[0355] Above-cited U.S. Pat. No. 5,340,564.

[0356] Above-cited U.S. Pat. No. 5,346,702.

[0357] Above-cited U.S. Pat. No. 5,352,459.

[0358] Above-cited U.S. Pat. No. 5,429,824.

[0359] Above-cited U.S. Pat. No. 5,503,723.

[0360] Above-cited U.S. Pat. No. 5,510,118.

[0361] Above-cited U.S. Pat. No. 5,534,270.

[0362] Above-cited U.S. Pat. No. 5,552,160.

[0363] Above-cited U.S. Pat. No. 5,573,783.

[0364] Above-cited U.S. Pat. No. 5,585,108.

[0365] Above-cited U.S. Pat. No. 5,591,456.

[0366] Above-cited U.S. Pat. No. 5,662,883.

[0367] Above-cited U.S. Pat. No. 5,665,331.

[0368] In general, however, the smaller the drug particle size, the moregrinding or milling time, energy and labor is required to produce theparticles and consequently, the more costly and less efficient is theprocess. Thus, smaller nano-sized drug particles are generallysignificantly more expensive and labor-intensive to produce in quantitythan larger nano-sized drug particles.

[0369] Surprisingly, we have now discovered that a selective COX-2inhibitory drug composition having a weight average particle size ofabout 450 nm to about 1000 nm (referred to herein as a “sub-micron”formulation and particle size) exhibits onset time and bioavailabilitysubstantially equal to that of a comparative composition having a weightaverage particle size of about 200 to about 400 nm, as measured in vitroand in vivo. The sub-micron formulation requires less milling time andenergy than the formulation comprising smaller nanoparticles with aweight average particle size in the 200-400 nm range.

[0370] It is further contemplated that certain advantages in addition tocost saving are obtainable with sub-micron as opposed to smallerparticle sizes. For example, in situations where ultra-fine particlestend to agglomerate or fail to disperse in the gastrointestinal fluid,the slightly larger sub-micron particles can exhibit enhanceddispersion.

[0371] Accordingly, in a particularly preferred embodiment of thepresent invention, there is provided a pharmaceutical compositioncomprising one or more orally deliverable dose units, each comprising aselective COX-2 inhibitory drug of low water solubility in atherapeutically effective amount, wherein the drug is present in solidparticles having a D₂₅ particle size of about 450 nm to about 1000 nm,and more preferably about 500 nm to about 900 nm, the compositionproviding at least a substantially similar C_(max) and/or at most asubstantially similar T_(max) by comparison with an otherwise similarcomposition having a D₂₅ particle size of less than 400 nm, and/orproviding a substantially greater C_(max) and/or a substantially shorterT_(max) by comparison with an otherwise similar composition having a D₂₅particle size larger than 1000 nm.

[0372] There is also provided a pharmaceutical composition comprisingone or more orally deliverable dose units, each comprising a selectiveCOX-2 inhibitory drug of low water solubility in a therapeuticallyeffective amount, wherein the drug is present in solid particles, about25% to 100% by weight of which have a particle size of about 450 nm toabout 1000 nm, more preferably about 500 nm to about 900 nm.

[0373] There is also provided a pharmaceutical composition comprisingone or more orally deliverable dose units, each comprising a selectiveCOX-2 inhibitory drug of low water solubility in a therapeuticallyeffective amount, wherein the drug is present in solid particles havinga weight average particle size of about 450 nm to about 1000 nm, andmore preferably about 500 nm to about 900 nm, the composition providingat least a substantially similar C_(max) and/or at most a substantiallysimilar T_(max) by comparison with an otherwise similar compositionhaving a weight average particle size of less than 400 nm, and/orproviding a substantially greater C_(max) and/or a substantially shorterT_(max) by comparison with an otherwise similar composition having aweight average particle size larger than 1000 nm. For purposes of thisdescription, “weight average particle size” can be considered synonymouswith D₅₀ particle size.

[0374] Sub-micron particles of a selective COX-2 inhibitory drug can beprepared by modification of processes described hereinabove forpreparation of nanoparticles, or by a process as illustratively setforth in Example 1 below.

EXAMPLES Example 1

[0375] Dispersions D1-D4 containing 5% by weight celecoxib were preparedby the process described below. The dispersions differed only in theparticle size range of the celecoxib.

[0376] 1. Celecoxib was micronized in an air jet mill to form a drugpowder.

[0377] 2. The drug powder was added to an aqueous solution containing2.5% low viscosity hydroxypropylcellulose (HPC-SL) and 0.12% sodiumdodecyl sulfate, to form a suspension.

[0378] 3. The suspension was wet milled to form an intermediatedispersion according to the following protocol. A sample amount of 6.0ml of the suspension (containing 20% celecoxib), a magnetic stir bar, 8ml of lead-free glass beads, and 50 μl of antifoaming agent (SigmaAntifoam A Concentrate) were added to a 20 ml scintillation vial. Toprovide an intermediate dispersion having a target particle size rangeof 6-7 μm (i.e., the size range achieved in the micronizing step, usedto provide a comparative composition), the vial was shaken for twominutes. To provide intermediate dispersions having smaller targetparticle size ranges, the vial was suspended over a high-strengthrotating magnet so that milling occurred by agitation of the glass beadsby rotation of the magnetic stir bar. Target particle size ranges werevaried by controlling magnet rotation rate, milling time and/or beadsize, as shown in Table 1. Small aliquots were removed at intervals inorder to monitor progress of particle size reduction.

[0379] 4. The resulting intermediate dispersion in each case wastransferred to a larger vial and diluted with fresh vehicle to form afinal dispersion. Nominal celecoxib concentration in the finaldispersions was 5% by weight. TABLE 1 Milling conditions used to producecelecoxib dispersions D1-D4. Target size Bead size Milling time Millingspeed Dispersion range (μm) (mm) (min) (rpm) D1 6-7 3.3-3.6 — — D2 1-33.3-3.6 26  900 D3 0.5-0.9 1.25-1.55 25  900 D4 0.2-0.4 0.5 52 1250

Example 2

[0380] Celecoxib particle size in dispersions D1-D4 as prepared inExample 1 was determined by laser (Fraunhofer) diffraction and byoptical microscopy.

[0381] Fraunhofer scattering was measured on static dispersion samplesusing a Sympatec spectrometer. Samples were diluted with water into astatic cell at a concentration that maintained a reduction in laserintensity of approximately 20%. The choice of collection lens wasdetermined by the population of large material present in suspension,and thus was different for each sample. However, the smallest focallength optic appropriate was used in each case. No Mie scatteringcorrections were applied. The results, presented in FIG. 1, show a D₅₀particle size consistent with the target size range. D₅₀ and otherparticle size parameters shown in FIG. 1 are believed to beoverestimated for the 0.2-0.4 μm celecoxib dispersion, since this sizerange is at the very limit of detection by this technique.

[0382] In order to visually confirm particle sizes, optical microscopywas used. Observations were carried out using an Olympus BH-2 microscopewith attached video camera. Images were then digitized (Snappy 4.0; PlayInc., Rancho Cordova, Calif.) and manipulated (Paint Shop Pro 6.02;JASC, Eden Prairie, Minn.) as appropriate. FIG. 2 shows micrographs ofsamples taken from celecoxib dispersions D1-D4 with non-polarized (left)and polarized (right) light. The bar represents 10 μm. SignificantBrownian motion was observed in dispersions D3 and D4, an observationconsistent with presence of very small nanoparticles. In contrast, onlyslight Brownian motion was noted in dispersion D2 and none at all indispersion D1.

Example 3

[0383] Dissolution characteristics of celecoxib crystals in dispersionsD1-D4 of Example 1 were evaluated in an in vitro dissolution assayperformed as described below. FIG. 4 is a schematic representation ofthe apparatus used in this experiment. The dissolution vessel is a 600ml jacketed beaker. The jacket is connected to a temperature-controlledwater circulator, which serves to maintain the temperature of thedissolution fluid at 37° C. A standard USP II dissolution paddle isutilized to stir the dissolution fluid. The paddle is driven by acomputer-controlled constant-velocity motor, which is set to operate at75 rpm throughout the course of the assay.

[0384] Dispersion samples are injected into the dissolution vessel justbelow the surface of the dissolution fluid. A sample is introduced inthis way to minimize likelihood that particles become trapped on thesurface of the fluid. Simultaneously, a data acquisition program isinitiated. A sample point is taken at 30 seconds and then every 30seconds thereafter for the duration of the assay. Dissolution progressis then followed for 60 minutes for each sample studied. Theconcentration of dissolved drug in the vessel is monitored via an insitu fiber-optic probe, which measures the optical absorbance ofdissolved drug in the dissolution fluid. The probe remains submerged inthe fluid throughout the course of the assay. The concentration ofdissolved drug in the fluid is determined from the measured absorbancevalues according to the Beer-Lambert equation $c = \frac{A}{1 \cdot ɛ}$

[0385] where A is the measured absorbance at 254 nm, 1 is the pathlength of the probe in cm, ε is the absorption coefficient at 254 nm inml/(μg.cm), and c is drug concentration in μg/ml. The path length of thefiber-optic probe is fixed at 1 cm. A typical calibration procedureusing a standard solution of celecoxib is used to determine theabsorption coefficient at 254 nm.

[0386] An attached personal computer is configured to record anabsorbance value every 30 seconds. Thus an experimental data setconsists of in situ absorbance values at 30-second intervals for theentire course of the experiment. The absorbance values are thenconverted to drug concentration via the Beer-Lambert equation above.

[0387] Prior to analyzing dispersions of the invention, a dissolutionvessel was filled with 500 ml of dissolution fluid (deionized water),and allowed to equilibrate to 37° C. A dissolution paddle andfiber-optic probe were placed into the vessel and also allowed toequilibrate to 37° C. Celecoxib dispersions D1-D4 prepared as in Example1 were sonicated for approximately 5 minutes before assay. Eachdispersion was hand shaken and immediately thereafter a 40 μl sample ofthe dispersion was extracted with a micropipette for placement in thedissolution fluid as described above.

[0388]FIG. 3 shows dissolution rates of dispersions D1-D4. To facilitatecomparison, all of the dissolution traces are normalized to the samevalue at 60 min. This normalization step is necessary, when comparingvery similar dissolution profiles, to compensate for small variations insample volume. The plot shows the normalized percentage of celecoxibdissolved as a function of time.

[0389] Overall, comparative dispersion D1 dissolved much more slowlythan did dispersions D2, D3 and D4 of the present invention, all ofwhich dissolved at substantially similar rates. This result suggeststhat there is no significant functional advantage in dissolution rate tobe obtained by milling celecoxib particles to a weight average particlesize less than 400 nm as compared to a weight average particle size inthe 450 nm to 1000 nm range. All nanoparticulate dispersions show asignificant advantage in dissolution rate by comparison with themicronized celecoxib dispersion.

Example 4

[0390] Pharmacokinetic properties of celecoxib dispersions D1-D4prepared as in Example 1 were evaluated in an in vivo dog study.

[0391] Eight male beagle dogs were given a 10 mg/kg dose of each of thefour celecoxib dispersions D1-D4. Venous blood was collected pre-dose,and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, and 24 hours post dose.Plasma was separated from blood by centrifugation and plasma drugconcentration was determined by high performance liquid chromatography.The resulting pharmacokinetic data are shown in Table 2. TABLE 2Pharmacokinetic parameters of celecoxib dispersions D1-D4 Dispersion D1D2 D3 D4 T_(max) (h) 1.2 0.84 0.72 0.72 C_(max) (ng/ml) 1400 4850 61206310 AUC (h*ng/ml) 14600 32700 37500 43500

[0392] (target particle size range 0.5-0.9 μm) and D4 (target particlesize range 0.2-0.4 μm) were very similar. Dispersion D2 (target particlesize range 1-3 μm) exhibited slightly longer T_(max) and moderatelylower C_(max) and AUC values than dispersions D4 and D3. T_(max) ofdispersion D1 was much longer, i.e., substantially longer, and C_(max)and AUC were much lower, i.e., substantially lower, than those ofdispersions D2, D3 and D4.

[0393] These results suggest that where fast onset therapeutic effect isdesired, good bioavailability will be obtained with celecoxib milled toa target particle size range of 0.5-0.9 μm and a D₅₀ particle size asdetermined by Fraunhofer scattering (FIG. 1) of about 0.9 μm. Nosignificant benefit is gained by expending additional time and energy tomill celecoxib particles to a target particle size range of 0.2-0.4 μm.

Example 5

[0394] Two celecoxib/caffeine suspensions were prepared by the processdescribed below.

[0395] 1. PVP (K30, 1.125%) was added to water to form a PVP solution;12 ml of the PVP solution were drawn in duplicate and placed into eachof two vessels (A and B).

[0396] 2. A 180 mg aliquot of caffeine was added to vessel A and a 900mg aliquot of caffeine was added to vessel B to form caffeinesuspensions A and B, respectively; both caffeine suspensions weresonicated as necessary.

[0397] 3. A celecoxib suspension (in water) was prepared comprising 30%celecoxib and 1.125% PVP (K30); the celecoxib suspension was wet milledusing a Dynomill to form a milled celecoxib suspension.

[0398] 4. Six ml of the milled celecoxib suspension were drawn induplicate and were individually added to each of caffeine suspensions Aand B to form celecoxib/caffeine suspensions A and B, respectively.

Example 6

[0399] Two solid celecoxib/caffeine compositions were prepared by theprocess described below.

[0400] 1. Fifteen ml each of celecoxib/caffeine suspension A and B ofExample 5 were drawn and placed into separate empty vessels.

[0401] 2. Lactose (1.5 g) and 15 mg of sodium lauryl sulfate were addedto each vessel with stirring to form intermediate suspensions A and B,respectively.

[0402] 3. Intermediate suspensions A and B were individually spray driedusing an apparatus consisting of an airbrush spray gun with anatomizing-air supply system set at 10 PSI, according to the followingprocedure: (a) the spray gun was positioned approximately six inchesfrom a glass plate; (b) heated dry air (from a heat gun) was supplied tothe surface of the glass plate to obtain a resulting plate temperatureof about 39-41° C.; (c) 15 ml of an intermediate suspension wasdelivered to the spray gun at a rate of 0.4-1.0 g/minute using aconstant flow syringe pump; (d) solid celecoxib/caffeine composition wascollected on the glass plate and was then removed with a single edgedrazor blade and collected in a vial.

What is claimed is:
 1. A pharmaceutical composition comprising one ormore orally deliverable dose units, each comprising (a) a selectivecyclooxygenase-2 inhibitory drug of low water solubility wherein thedrug is present in solid particles having a D₉₀ particle size of about0.01 μm to about 200 μm, a sufficient portion by weight of the particlesbeing smaller than 1 μm to provide a substantially higher C_(max) and/ora substantially shorter T_(max) and/or a substantially shorter time toreach a threshold blood serum concentration for therapeutic effect, bycomparison with an otherwise similar composition wherein substantiallyall of the particles are larger than 1 μm, and (b) a second drugselected from vasomodulators and alkylxanthine compounds; wherein theselective cyclooxygenase-2 inhibitory drug and the second drug arepresent in total and relative amounts effective to relieve pain.
 2. Thecomposition of claim 1 wherein the second drug is an alkylxanthinecompound.
 3. The composition of claim 2 wherein the alkylxanthinecompound is selected from caffeine, theophylline and theobromine.
 4. Thecomposition of claim 2 wherein the alkylxanthine compound is caffeine.5. The composition of claim 1 having total bioavailability of saidselective cyclooxygenase-2 inhibitory drug that is greater than that ofan otherwise similar composition wherein substantially all of saidselective cyclooxygenase-2 inhibitory drug particles are larger than 1μm.
 6. The composition of claim 1 exhibiting a substantially shortertime to reach a therapeutically effective threshold blood serumconcentration of said selective cyclooxygenase-2 inhibitory drug, bycomparison with an otherwise similar composition wherein substantiallyall of the selective cyclooxygenase-2 inhibitory drug particles arelarger than 1 μm.
 7. The composition of claim 1 wherein substantiallyall of said selective cyclooxygenase-2 inhibitory drug particles aresmaller than 1 μm.
 8. The composition of claim 1 wherein the dose unitsare in the form of discrete solid articles.
 9. The composition of claim8 wherein the solid articles are tablets or capsules.
 10. Thecomposition of claim 1 that is in the form of a substantiallyhomogeneous flowable mass from which single dose units are measurablyremovable.
 11. The composition of claim 10 wherein the substantiallyhomogeneous flowable mass is a liquid suspension.
 12. The composition ofclaim 1 wherein said solid selective cyclooxygenase-2 inhibitory drugparticles have a D₂₅ particle size of about 450 nm to about 1000 nm. 13.The composition of claim 1 wherein about 25% to 100% by weight of saidsolid selective cyclooxygenase-2 inhibitory drug particles have aparticle size of about 450 nm to about 1000 nm.
 14. The composition ofclaim 1 wherein said solid selective cyclooxygenase-2 inhibitory drugparticles have a weight average particle size of about 450 nm to about1000 nm.
 15. The composition of claim 1 wherein the selectivecyclooxygenase-2 inhibitory drug is a compound of formula

where R³ is a methyl or amino group, R⁴ is hydrogen or a C₁₋₄ alkyl oralkoxy group, X is N or CR⁵ where R⁵ is hydrogen or halogen, and Y and Zare independently carbon or nitrogen atoms defining adjacent atoms of afive- to six-membered ring that is unsubstituted or substituted at oneor more positions with oxo, halo, methyl or halomethyl groups.
 16. Thecomposition of claim 15 wherein the five- to six-membered ring isselected from the group consisting of cyclopentenone, furanone,methylpyrazole, isoxazole and pyridine rings substituted at no more thanone position.
 17. The composition of claim 1 wherein the selectivecyclooxygenase-2 inhibitory drug is selected from the group consistingof celecoxib, deracoxib, valdecoxib, rofecoxib,5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine,2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-oneand (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.
 18. The composition of claim 17 wherein the selectivecyclooxygenase-2 inhibitory drug is celecoxib.
 19. The composition ofclaim 18 comprising about 10 mg to about 1000 mg celecoxib in each doseunit.
 20. A method of analgesia comprising orally administering, to asubject in need of analgesia, (a) a first pharmaceutical compositioncomprising one or more orally deliverable dose units, each comprising aselective cyclooxygenase-2 inhibitory drug of low water solubility in atherapeutically effective amount, wherein the drug is present in solidparticles having a D₉₀ particle size of about 0.01 μm to about 200 μm, asufficient portion by weight of the particles being smaller than 1 μm toprovide a substantially higher C_(max) and/or a substantially shorterT_(max) and/or a substantially shorter time to reach a threshold bloodserum concentration for therapeutic effect, by comparison with anotherwise similar composition wherein substantially all of the particlesare larger than 1 μm, and (b) a second pharmaceutical compositioncomprising a vasomodulator and/or an alkylxanthine compound; wherein thefirst and second compositions are administered in total and relativeamounts effective to relieve pain.
 21. The method of claim 20 whereinthe second composition comprises an alkylxanthine compound.
 22. Themethod of claim 21 wherein the alkylxanthine compound is selected fromcaffeine, theophylline and theobromine.
 23. The method of claim 21wherein the alkylxanthine compound is caffeine.
 24. The method of claim20 wherein the subject suffers from headache or migraine and wherein thefirst and second compositions are administered in total and relativeamounts effective to relieve pain in the headache or migraine.
 25. Themethod of claim 20 wherein the first and second compositions areadministered at substantially the same time.
 26. The method of claim 20wherein the first and second compositions are administered atsubstantially different times.
 27. A method of analgesia comprisingorally administering, to a subject in need of analgesia, an effectivepain-relieving amount of a composition of claim
 1. 28. The method ofclaim 27 wherein the subject suffers from headache or migraine andwherein said composition is administered in an amount effective torelieve pain in the headache or migraine.
 29. A pharmaceuticalcomposition comprising one or more orally deliverable dose units, eachcomprising (a) a selective cyclooxygenase-2 inhibitory drug of low watersolubility, wherein the drug is present in solid particles having a D₉₀particle size of about 0.01 μm to about 200 μm, and wherein about 25% to100% by weight of the particles are smaller than 1 μm, and (b) a seconddrug selected from vasomodulators and alkylxanthine compounds; whereinthe selective cyclooxygenase-2 inhibitory drug and the second drug arepresent in total and relative amounts effective to relieve pain.
 30. Thecomposition of claim 29 wherein the second drug is an alkylxanthinecompound.
 31. The composition of claim 30 wherein the alkylxanthinecompound is selected from caffeine, theophylline and theobromine. 32.The composition of claim 30 wherein the alkylxanthine compound iscaffeine.
 33. The composition of claim 29 wherein substantially all ofsaid solid selective cyclooxygenase-2 inhibitory drug particles aresmaller than 1 μm.
 34. The composition of claim 29 wherein the doseunits are in the form of discrete solid articles.
 35. The composition ofclaim 34 wherein the solid articles are tablets or capsules.
 36. Thecomposition of claim 29 that is in the form of a substantiallyhomogeneous flowable mass from which single dose units are measurablyremovable.
 37. The composition of claim 36 wherein the substantiallyhomogeneous flowable mass is a liquid suspension.
 38. The composition ofclaim 29 wherein said solid selective cyclooxygenase-2 inhibitory drugparticles have a D₂₅ particle size of about 450 nm to about 1000 nm. 39.The composition of claim 29 wherein about 25% to 100% by weight of saidsolid selective cyclooxygenase-2 inhibitory drug particles have aparticle size of about 450 nm to about 1000 nm.
 40. The composition ofclaim 29 wherein said solid selective cyclooxygenase-2 inhibitory drugparticles have a weight average particle size of about 450 nm to about1000 nm.
 41. The composition of claim 29 wherein the selectivecyclooxygenase-2 inhibitory drug is a compound of formula

where R³ is a methyl or amino group, R⁴ is hydrogen or a C₁₋₄ alkyl oralkoxy group, X is N or CR⁵ where R⁵ is hydrogen or halogen, and Y and Zare independently carbon or nitrogen atoms defining adjacent atoms of afive- to six-membered ring that is unsubstituted or substituted at oneor more positions with oxo, halo, methyl or halomethyl groups.
 42. Thecomposition of claim 41 wherein the five- to six-membered ring isselected from the group consisting of cyclopentenone, furanone,methylpyrazole, isoxazole and pyridine rings substituted at no more thanone position.
 43. The composition of claim 29 wherein the selectivecyclooxygenase-2 inhibitory drug is selected from the group consistingof celecoxib, deracoxib, valdecoxib, rofecoxib,5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine,2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-oneand (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylicacid.
 44. The composition of claim 43 wherein the selectivecyclooxygenase-2 inhibitory drug is celecoxib.
 45. The composition ofclaim 44 comprising about 10 mg to about 1000 mg celecoxib in each doseunit.
 46. A method of analgesia comprising orally administering, to asubject in need of analgesia, (a) a first pharmaceutical compositioncomprising one or more orally deliverable dose units, each comprising aselective cyclooxygenase-2 inhibitory drug of low water solubility in atherapeutically effective amount, wherein the drug is present in solidparticles having a D₉₀ particle size of about 0.01 μm to about 200 μm,wherein about 25% to 100% by weight of the particles are smaller than 1μm, and (b) a second pharmaceutical composition comprising avasomodulator and/or an alkylxanthine compound; wherein the first andsecond compositions are administered in total and relative amountseffective to relieve pain.
 47. The method of claim 46 wherein the secondcomposition comprises an alkylxanthine compound.
 48. The method of claim47 wherein the alkylxanthine compound is selected from caffeine,theophylline and theobromine.
 49. The method of claim 47 wherein thealkylxanthine compound is caffeine.
 50. The method of claim 46 whereinthe subject suffers from headache or migraine and wherein the first andsecond compositions are administered in total and relative amountseffective to relieve pain in the headache or migraine.
 51. The method ofclaim 46 wherein the first and second compositions are administered atsubstantially the same time.
 52. The method of claim 46 wherein thefirst and second compositions are administered at substantiallydifferent times.
 53. A method of analgesia comprising orallyadministering, to a subject in need of analgesia, an effectivepain-relieving amount of a composition of claim
 29. 54. The method ofclaim 53 wherein the subject suffers from headache or migraine andwherein said composition is administered in an amount effective torelieve pain in the headache or migraine.
 55. A pharmaceuticalcomposition comprising one or more orally deliverable dose units, eachcomprising (a) a selective cyclooxygenase-2 inhibitory drug of low watersolubility wherein the drug is present in solid particles having a D₉₀particle size of about 0.01 μm to about 200 μm, a sufficient portion byweight of the particles being smaller than 1 μm to provide asubstantially higher C_(max) and/or a substantially shorter T_(max)and/or a substantially shorter time to reach a threshold blood serumconcentration for therapeutic effect, by comparison with an otherwisesimilar composition in which at least 80% of the drug by weight is inthe form of particles larger than 1 μm and smaller than 10 μm, and (b) asecond drug selected from vasomodulators and alkylxanthine compounds;wherein the selective cyclooxygenase-2 inhibitory drug and the seconddrug are present in total and relative amounts effective to relievepain.
 56. A pharmaceutical composition comprising one or more orallydeliverable dose units, each comprising (a) nanoparticles of a selectivecyclooxygenase-2 inhibitory drug of low water solubility wherein thedrug is present in nanoparticle form in an amount to provide asubstantially higher C_(max) and/or a substantially shorter T_(max)and/or a substantially shorter time to reach a threshold blood serumconcentration for therapeutic effect, by comparison with an otherwisesimilar composition containing the same amount of drug as is present inthe nanoparticles wherein at least 80% of the drug by weight in theotherwise similar composition is in the form of particles larger than 1μm and smaller than 10 μm, and (b) a second drug selected fromvasomodulators and alkylxanthine compounds; wherein the selectivecyclooxygenase-2 inhibitory drug and the second drug are present intotal and relative amounts effective to relieve pain.
 57. A method ofanalgesia comprising orally administering, to a subject in need ofanalgesia, (a) a first pharmaceutical composition comprising one or moreorally deliverable dose units, each comprising a selectivecyclooxygenase-2 inhibitory drug of low water solubility in atherapeutically effective amount, wherein the drug is present in solidparticles having a D₉₀ particle size of about 0.01 μm to about 200 μm, asufficient portion by weight of the particles being smaller than 1 μm toprovide a substantially higher C_(max) and/or a substantially shorterT_(max) and/or a substantially shorter time to reach a threshold bloodserum concentration for therapeutic effect, by comparison with anotherwise similar composition in which at least 80% of the drug byweight is in the form of particles larger than 1 μm and smaller than 10μm, and (b) a second pharmaceutical composition comprising avasomodulator and/or an alkylxanthine compound; wherein the first andsecond compositions are administered in total and relative amountseffective to relieve pain.
 58. A method of analgesia comprising orallyadministering, to a subject in need of analgesia, (a) a firstpharmaceutical composition comprising one or more orally deliverabledose units, each comprising nanoparticles of a selectivecyclooxygenase-2 inhibitory drug of low water solubility wherein thedrug is present in nanoparticle form in an amount to provide asubstantially higher C_(max) and/or a substantially shorter T_(max)and/or a substantially shorter time to reach a threshold blood serumconcentration for therapeutic effect, by comparison with an otherwisesimilar composition containing the same amount of drug as is present inthe nanoparticles wherein at least 80% of the drug by weight in theotherwise similar composition is in the form of particles larger than 1μm and smaller than 10 μm, and (b) a second pharmaceutical compositioncomprising a vasomodulator and/or an alkylxanthine compound; wherein thefirst and second compositions are administered in total and relativeamounts effective to relieve pain.